Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure

Circulation Research

Volumn 118, Issue 8, 2016, Pages 1313-1326

  Patel, Vaibhav B ^a   Zhong, Jiu Chang ^b,c   Grant, Maria B ^d   Oudit, Gavin Y ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

^b SHANGHAI JIAO TONG UNIVERSITY SCHOOL OF MEDICINE   (China)

^c Shanghai Key Laboratory of Hypertension Shanghai Institute of Hypertension   (China)

^d INDIANA UNIVERSITY   (United States)

Author keywords

angiotensin 1 7; angiotensin II; angiotensin converting enzyme 2; heart failure; renin angiotensin system

Indexed keywords

ANGIOTENSIN[1-7]; BETA SECRETASE 2; ANGIOTENSIN CONVERTING ENZYME 2; ANGIOTENSIN I; ANGIOTENSIN I (1-7); DIPEPTIDYL CARBOXYPEPTIDASE; PEPTIDE FRAGMENT;

ANGIOTENSIN BLOOD LEVEL; BIOCHEMISTRY; CARDIAC MUSCLE CELL; CARDIOMYOPATHY; CAUSE OF DEATH; DIABETES MELLITUS; DISEASE COURSE; ENDOTHELIUM CELL; HEART EJECTION FRACTION; HEART FAILURE; HYPERTENSION; OBESITY; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEGRADATION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; ANIMAL; HUMAN; METABOLISM; PHYSIOLOGY; SIGNAL TRANSDUCTION;

ANGIOTENSIN I; ANIMALS; HEART FAILURE; HUMANS; PEPTIDE FRAGMENTS; PEPTIDYL-DIPEPTIDASE A; RENIN-ANGIOTENSIN SYSTEM; SIGNAL TRANSDUCTION;

EID: 84963808130     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.116.307708     Document Type: Review

References (161)

1. Givertz MM, Manipulation of the renin-angiotensin system. Circulation 2001 104 E14 E18
2. Zaman MA, Oparil S, Calhoun DA, Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 2002 1 621 636. doi: 10.1038/nrd873
3. Bader M, Ganten D, Update on tissue renin-angiotensin systems. J Mol Med (Berl) 2008 86 615 621. doi: 10.1007/s00109-008-0336-0
4. Dzau VJ, Re R, Tissue angiotensin system in cardiovascular medicine. A paradigm shift? Circulation 1994 89 493 498
5. Lavoie JL, Sigmund CD, Minireview: overview of the renin-angiotensin system-an endocrine and paracrine system. Endocrinology 2003 144 2179 2183. doi: 10.1210/en.2003-0150
6. Paul M, Poyan Mehr A, Kreutz R, Physiology of local renin-angiotensin systems. Physiol Rev 2006 86 747 803. doi: 10.1152/physrev.00036.2005
7. Crackower MA, Sarao R, Oudit GY, Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002 417 822 828. doi: 10.1038/nature00786
8. Danser AH, Schalekamp MA, Is there an internal cardiac renin-angiotensin system? Heart 1996 76 28 32
9. Paul M, Wagner J, Dzau VJ, Gene expression of the renin-angiotensin system in human tissues. Quantitative analysis by the polymerase chain reaction. J Clin Invest 1993 91 2058 2064. doi: 10.1172/JCI116428
10. Tahmasebi M, Puddefoot JR, Inwang ER, Vinson GP, The tissue renin-angiotensin system in human pancreas. J Endocrinol 1999 161 317 322
11. Wagner J, Jan Danser AH, Derkx FH, de Jong TV, Paul M, Mullins JJ, Schalekamp MA, Ganten D, Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system. Br J Ophthalmol 1996 80 159 163
12. Tikellis C, Johnston CI, Forbes JM, Burns WC, Thomas MC, Lew RA, Yarski M, Smith AI, Cooper ME, Identification of angiotensin converting enzyme 2 in the rodent retina. Curr Eye Res 2004 29 419 427. doi: 10.1080/02713680490517944
13. Baltatu O, Silva JA Jr, Ganten D, Bader M, The brain renin-angiotensin system modulates angiotensin II-induced hypertension and cardiac hypertrophy. Hypertension 2000 35 409 412
14. Ribeiro-Oliveira A Jr, Nogueira AI, Pereira RM, Boas WW, Dos Santos RA, Simões e Silva AC, The renin-angiotensin system and diabetes: an update. Vasc Health Risk Manag 2008 4 787 803
15. Mercure C, Yogi A, Callera GE, Aranha AB, Bader M, Ferreira AJ, Santos RA, Walther T, Touyz RM, Reudelhuber TL, Angiotensin(1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res 2008 103 1319 1326
16. Oudit GY, Penninger JM, Recombinant human angiotensin-converting enzyme 2 as a new renin-angiotensin system peptidase for heart failure therapy. Curr Heart Fail Rep 2011 8 176 183. doi: 10.1007/s11897-011-0063-7
17. Alenina N, Xu P, Rentzsch B, Patkin EL, Bader M, Genetically altered animal models for Mas and angiotensin-(1-7). Exp Physiol 2008 93 528 537. doi: 10.1113/expphysiol.2007.040345
18. Bader M, ACE2, angiotensin-(1-7), and Mas: the other side of the coin. Pflugers Arch 2013 465 79 85
19. Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM, Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension 2007 49 185 192. doi: 10.1161/01.HYP.0000251865.35728.2f
20. Santos RA, Simoes e Silva AC, Maric C, Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A 2003 100 8258 8263. doi: 10.1073/pnas.1432869100
21. Tallant EA, Ferrario CM, Gallagher PE, Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol 2005 289 H1560 H1566. doi: 10.1152/ajpheart.00941.2004
22. Zhang Y, Li B, Wang B, Zhang J, Wu J, Morgan T, Alteration of cardiac ACE2/Mas expression and cardiac remodelling in rats with aortic constriction. Chin J Physiol 2014 57 335 342. doi: 10.4077/CJP.2014.BAD268
23. Flores-Muñoz M, Godinho BM, Almalik A, Nicklin SA, Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin type 2 receptor. PLoS One 2012 7 e45564. doi: 10.1371/journal.pone.0045564
24. Flores-Munoz M, Work LM, Douglas K, Denby L, Dominiczak AF, Graham D, Nicklin SA, Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor. Hypertension 2012 59 300 307. doi: 10.1161/HYPERTENSIONAHA.111.177485
25. Ocaranza MP, Lavandero S, Jalil JE, Moya J, Pinto M, Novoa U, Apablaza F, Gonzalez L, Hernandez C, Varas M, Lopez R, Godoy I, Verdejo H, Chiong M, Angiotensin-(1-9) regulates cardiac hypertrophy in vivo and in vitro. J Hypertens 2010 28 1054 1064
26. Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE, Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension. J Hypertens 2011 29 706 715. doi: 10.1097/HJH.0b013e3283440665
27. Oudit GY, Crackower MA, Backx PH, Penninger JM, The role of ACE2 in cardiovascular physiology. Trends Cardiovasc Med 2003 13 93 101
28. Lo J, Patel VB, Wang Z, Levasseur J, Kaufman S, Penninger JM, Oudit GY, Angiotensin-converting enzyme 2 antagonizes angiotensin II-induced pressor response and NADPH oxidase activation in Wistar-Kyoto rats and spontaneously hypertensive rats. Exp Physiol 2013 98 109 122. doi: 10.1113/expphysiol.2012.067165
29. Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, Tsushima RG, Scholey JW, Khokha R, Penninger JM, Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res 2007 75 29 39. doi: 10.1016/j.cardiores.2007.04.007
30. Patel VB, Bodiga S, Fan D, Das SK, Wang Z, Wang W, Basu R, Zhong J, Kassiri Z, Oudit GY, Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2-null mice. Hypertension 2012 59 1195 1203. doi: 10.1161/HYPERTENSIONAHA.112.191650
31. Danilczyk U, Penninger JM, Angiotensin-converting enzyme II in the heart and the kidney. Circ Res 2006 98 463 471. doi: 10.1161/01.RES.0000205761.22353.5f
32. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S, A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000 87 E1 E9
33. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ, A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000 275 33238 33243. doi: 10.1074/jbc.M002615200
34. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M, Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003 426 450 454. doi: 10.1038/nature02145
35. Warner FJ, Lew RA, Smith AI, Lambert DW, Hooper NM, Turner AJ, Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J Biol Chem 2005 280 39353 39362. doi: 10.1074/jbc.M508914200
36. Turner AJ, Tipnis SR, Guy JL, Rice G, Hooper NM, ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors. Can J Physiol Pharmacol 2002 80 346 353
37. Rushworth CA, Guy JL, Turner AJ, Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis. FEBS J 2008 275 6033 6042. doi: 10.1111/j.1742-4658.2008.06733.x
38. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P, Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002 277 14838 14843. doi: 10.1074/jbc.M200581200
39. Guy JL, Jackson RM, Jensen HA, Hooper NM, Turner AJ, Identification of critical active-site residues in angiotensin-converting enzyme-2 (ACE2) by site-directed mutagenesis. FEBS J 2005 272 3512 3520. doi: 10.1111/j.1742-4658.2005.04756.x
40. Clarke NE, Turner AJ, Angiotensin-converting enzyme 2: the first decade. Int J Hypertens 2012 2012 307315. doi: 10.1155/2012/307315
41. Guy JL, Jackson RM, Acharya KR, Sturrock ED, Hooper NM, Turner AJ, Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements, and chloride dependence. Biochemistry 2003 42 13185 13192. doi: 10.1021/bi035268s
42. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM, Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 2004 383 45 51. doi: 10.1042/BJ20040634
43. Dales NA, Gould AE, Brown JA, Calderwood EF, Guan B, Minor CA, Gavin JM, Hales P, Kaushik VK, Stewart M, Tummino PJ, Vickers CS, Ocain TD, Patane MA, Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors. J Am Chem Soc 2002 124 11852 11853
44. Rella M, Rushworth CA, Guy JL, Turner AJ, Langer T, Jackson RM, Structure-based pharmacophore design and virtual screening for novel angiotensin converting enzyme 2 inhibitors. J Chem Inf Model 2006 46 708 716. doi: 10.1021/ci0503614
45. Turner AJ, Hiscox JA, Hooper NM, ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci 2004 25 291 294. doi: 10.1016/j.tips.2004.04.001
46. Hashimoto T, Perlot T, Rehman A, ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012 487 477 481. doi: 10.1038/nature11228
47. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, Van Goor H, Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004 203 631 637. doi: 10.1002/path.1570
48. Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, Shaw T, Warner FJ, Zuilli A, Burrell LM, Angus PW, Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 2005 54 1790 1796. doi: 10.1136/gut.2004.062398
49. Doobay MF, Talman LS, Obr TD, Tian X, Davisson RL, Lazartigues E, Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 2007 292 R373 R381. doi: 10.1152/ajpregu.00292.2006
50. Wong DW, Oudit GY, Reich H, Kassiri Z, Zhou J, Liu QC, Backx PH, Penninger JM, Herzenberg AM, Scholey JW, Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol 2007 171 438 451. doi: 10.2353/ajpath.2007.060977
51. Kuba K, Imai Y, Rao S, Jiang C, Penninger JM, Lessons from SARS: control of acute lung failure by the SARS receptor ACE2. J Mol Med (Berl) 2006 84 814 820. doi: 10.1007/s00109-006-0094-9
52. Gembardt F, Sterner-Kock A, Imboden H, Spalteholz M, Reibitz F, Schultheiss HP, Siems WE, Walther T, Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents. Peptides 2005 26 1270 1277. doi: 10.1016/j.peptides.2005.01.009
53. Patel VB, Clarke N, Wang Z, Fan D, Parajuli N, Basu R, Putko B, Kassiri Z, Turner AJ, Oudit GY, Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS. J Mol Cell Cardiol 2014 66 167 176. doi: 10.1016/j.yjmcc.2013.11.017
54. Patel VB, Zhong JC, Fan D, Basu R, Morton JS, Parajuli N, McMurtry MS, Davidge ST, Kassiri Z, Oudit GY, Angiotensin-converting enzyme 2 is a critical determinant of angiotensin II-induced loss of vascular smooth muscle cells and adverse vascular remodeling. Hypertension 2014 64 157 164. doi: 10.1161/HYPERTENSIONAHA.114.03388
55. Santos RA, Castro CH, Gava E, Pinheiro SV, Almeida AP, Paula RD, Cruz JS, Ramos AS, Rosa KT, Irigoyen MC, Bader M, Alenina N, Kitten GT, Ferreira AJ, Impairment of in vitro and in vivo heart function in angiotensin-(1-7) receptor MAS knockout mice. Hypertension 2006 47 996 1002. doi: 10.1161/01.HYP.0000215289.51180.5c
56. Sampaio WO, Henrique de Castro C, Santos RA, Schiffrin EL, Touyz RM, Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension 2007 50 1093 1098. doi: 10.1161/HYPERTENSIONAHA.106.084848
57. Iwata M, Cowling RT, Gurantz D, Moore C, Zhang S, Yuan JX, Greenberg BH, Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. Am J Physiol Heart Circ Physiol 2005 289 H2356 H2363. doi: 10.1152/ajpheart.00317.2005
58. Black RA, Rauch CT, Kozlosky CJ, A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997 385 729 733. doi: 10.1038/385729a0
59. Moss ML, Jin SL, Milla ME, Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 1997 385 733 736. doi: 10.1038/385733a0
60. Gooz M, ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol 2010 45 146 169. doi: 10.3109/10409231003628015
61. Lambert DW, Clarke NE, Hooper NM, Turner AJ, Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain. FEBS Lett 2008 582 385 390. doi: 10.1016/j.febslet.2007.11.085
62. Iwata M, Silva Enciso JE, Greenberg BH, Selective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor alpha-converting enzyme. Am J Physiol Cell Physiol 2009 297 C1318 C1329. doi: 10.1152/ajpcell.00036.2009
63. Xia H, Sriramula S, Chhabra KH, Lazartigues E, Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension. Circ Res 2013 113 1087 1096. doi: 10.1161/CIRCRESAHA.113.301811
64. Salem ES, Grobe N, Elased KM, Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice. Am J Physiol Renal Physiol 2014 306 F629 F639. doi: 10.1152/ajprenal.00516.2013
65. Xu P, Derynck R, Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell 2010 37 551 566. doi: 10.1016/j.molcel.2010.01.034
66. Wang W, Patel VB, Parajuli N, Fan D, Basu R, Wang Z, Ramprasath T, Kassiri Z, Penninger JM, Oudit GY, Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease. J Mol Med (Berl) 2014 92 847 858. doi: 10.1007/s00109-014-1149-y
67. Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, Loibner H, Wang XH, Penninger JM, Kassiri Z, Oudit GY, Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation 2010 122 717 728. doi: 10.1161/CIRCULATIONAHA.110.955369
68. Epelman S, Tang WH, Chen SY, Van Lente F, Francis GS, Sen S, Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol 2008 52 750 754. doi: 10.1016/j.jacc.2008.02.088
69. Putko BN, Wang Z, Lo J, Anderson T, Becher H, Dyck JR, Kassiri Z, Oudit GY, Alberta HEART Investigators Alberta HEART Investigators Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology. PLoS One 2014 9 e99495. doi: 10.1371/journal.pone.0099495
70. Lambert DW, Lambert LA, Clarke NE, Hooper NM, Porter KE, Turner AJ, Angiotensin-converting enzyme 2 is subject to post-transcriptional regulation by miR-421. Clin Sci (Lond) 2014 127 243 249. doi: 10.1042/CS20130420
71. Clarke NE, Belyaev ND, Lambert DW, Turner AJ, Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress. Clin Sci (Lond) 2014 126 507 516. doi: 10.1042/CS20130291
72. Sato T, Suzuki T, Watanabe H, Kadowaki A, Fukamizu A, Liu PP, Kimura A, Ito H, Penninger JM, Imai Y, Kuba K, Apelin is a positive regulator of ACE2 in failing hearts. J Clin Invest 2013 123 5203 5211. doi: 10.1172/JCI69608
73. Hunter JJ, Chien KR, Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 1999 341 1276 1283. doi: 10.1056/NEJM199910213411706
74. Braunwald E, Bristow MR, Congestive heart failure: fifty years of progress. Circulation 2000 102 IV14 IV23
75. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009 119 e391 e479. doi: 10.1161/CIRCULATIONAHA.109.192065
76. Arnold JM, Liu P, Demers C, Canadian Cardiovascular Society Canadian Cardiovascular Society Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol 2006 22 23 45
77. Roger VL, Go AS, Lloyd-Jones DM, American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics-2012 update: a report from the American Heart Association. Circulation 2012 125 e2 e220. doi: 10.1161/CIR.0b013e31823ac046
78. Zimmet P, Alberti KG, Shaw J, Global and societal implications of the diabetes epidemic. Nature 2001 414 782 787. doi: 10.1038/414782a
79. Kannel WB, Hjortland M, Castelli WP, Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974 34 29 34
80. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC Jr, Sowers JR, Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999 100 1134 1146
81. Boudina S, Abel ED, Diabetic cardiomyopathy revisited. Circulation 2007 115 3213 3223. doi: 10.1161/CIRCULATIONAHA.106.679597
82. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS, Obesity and the risk of heart failure. N Engl J Med 2002 347 305 313. doi: 10.1056/NEJMoa020245
83. Kenchaiah S, Sesso HD, Gaziano JM, Body mass index and vigorous physical activity and the risk of heart failure among men. Circulation 2009 119 44 52. doi: 10.1161/CIRCULATIONAHA.108.807289
84. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM, Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006 355 251 259. doi: 10.1056/NEJMoa052256
85. Krauss RM, Winston M, Fletcher BJ, Grundy SM, Obesity: impact on cardiovascular disease. Circulation 1998 98 1472 1476
86. Kopelman PG, Obesity as a medical problem. Nature 2000 404 635 643. doi: 10.1038/35007508
87. From AM, Scott CG, Chen HH, The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol 2010 55 300 305. doi: 10.1016/j.jacc.2009.12.003
88. Hayashi T, Takai S, Yamashita C, Impact of the renin-angiotensin-aldosterone-system on cardiovascular and renal complications in diabetes mellitus. Curr Vasc Pharmacol 2010 8 189 197
89. Nakao YM, Teramukai S, Tanaka S, Yasuno S, Fujimoto A, Kasahara M, Ueshima K, Nakao K, Hinotsu S, Nakao K, Kawakami K, Effects of renin-angiotensin system blockades on cardiovascular outcomes in patients with diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 2012 96 68 75. doi: 10.1016/j.diabres.2011.11.025
90. Boudina S, Han YH, Pei S, Tidwell TJ, Henrie B, Tuinei J, Olsen C, Sena S, Abel ED, UCP3 regulates cardiac efficiency and mitochondrial coupling in high fat-fed mice but not in leptin-deficient mice. Diabetes 2012 61 3260 3269. doi: 10.2337/db12-0063
91. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX, Aziz S, Johnson JI, Bugger H, Zaha VG, Abel ED, Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 2007 56 2457 2466. doi: 10.2337/db07-0481
92. McMurray JJ, CONSENSUS to EMPHASIS: the overwhelming evidence which makes blockade of the renin-angiotensin-aldosterone system the cornerstone of therapy for systolic heart failure. Eur J Heart Fail 2011 13 929 936. doi: 10.1093/eurjhf/hfr093
93. Mehta PK, Griendling KK, Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007 292 C82 C97. doi: 10.1152/ajpcell.00287.2006
94. Latini R, Tognoni G, Maggioni AP, Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group. J Am Coll Cardiol 2000 35 1801 1807
95. Li M, Liu K, Michalicek J, Angus JA, Hunt JE, Dell'Italia LJ, Feneley MP, Graham RM, Husain A, Involvement of chymase-mediated angiotensin II generation in blood pressure regulation. J Clin Invest 2004 114 112 120. doi: 10.1172/JCI20805
96. Wei CC, Hase N, Inoue Y, Bradley EW, Yahiro E, Li M, Naqvi N, Powell PC, Shi K, Takahashi Y, Saku K, Urata H, Dell'italia LJ, Husain A, Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest 2010 120 1229 1239. doi: 10.1172/JCI39345
97. Jorde UP, Ennezat PV, Lisker J, Suryadevara V, Infeld J, Cukon S, Hammer A, Sonnenblick EH, Le Jemtel TH, Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000 101 844 846
98. Petrie MC, Padmanabhan N, McDonald JE, Hillier C, Connell JM, McMurray JJ, Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease. J Am Coll Cardiol 2001 37 1056 1061
99. Wysocki J, Ye M, Rodriguez E, González-Pacheco FR, Barrios C, Evora K, Schuster M, Loibner H, Brosnihan KB, Ferrario CM, Penninger JM, Batlle D, Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension 2010 55 90 98. doi: 10.1161/HYPERTENSIONAHA.109.138420
100. Patel VB, Takawale A, Ramprasath T, Das SK, Basu R, Grant MB, Hall DA, Kassiri Z, Oudit GY, Antagonism of angiotensin 1-7 prevents the therapeutic effects of recombinant human ACE2. J Mol Med (Berl) 2015 93 1003 1013. doi: 10.1007/s00109-015-1285-z
101. Shaltout HA, Westwood BM, Averill DB, Ferrario CM, Figueroa JP, Diz DI, Rose JC, Chappell MC, Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II. Am J Physiol Renal Physiol 2007 292 F82 F91. doi: 10.1152/ajprenal.00139.2006
102. Ocaranza MP, Godoy I, Jalil JE, Varas M, Collantes P, Pinto M, Roman M, Ramirez C, Copaja M, Diaz-Araya G, Castro P, Lavandero S, Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension 2006 48 572 578. doi: 10.1161/01.HYP.0000237862.94083.45
103. Ye M, Wysocki J, Gonzalez-Pacheco FR, Salem M, Evora K, Garcia-Halpin L, Poglitsch M, Schuster M, Batlle D, Murine recombinant angiotensin-converting enzyme 2: effect on angiotensin II-dependent hypertension and distinctive angiotensin-converting enzyme 2 inhibitor characteristics on rodent and human angiotensin-converting enzyme 2. Hypertension 2012 60 730 740. doi: 10.1161/HYPERTENSIONAHA.112.198622
104. ClinicalTrials.gov Safety and tolerability study of apn01 (recombinant human angiotensin converting enzyme 2). https://clinicaltrials.Gov/ct2/show/nct00886353. Nlm identifier: Nct00886353. Accessed January 2016
105. ClinicalTrials.gov The safety, tolerability, pk and pd of gsk2586881 in patients with acute lung injury. https://clinicaltrials.Gov/ct2/show/nct01597635. Nlm identifier: Nct00886353. Accessed January 2016
106. Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, Penninger J, Krähenbühl S, Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet 2013 52 783 792. doi: 10.1007/s40262-013-0072-7
107. Giani JF, Muñoz MC, Mayer MA, Veiras LC, Arranz C, Taira CA, Turyn D, Toblli JE, Dominici FP, Angiotensin-(1-7) improves cardiac remodeling and inhibits growth-promoting pathways in the heart of fructose-fed rats. Am J Physiol Heart Circ Physiol 2010 298 H1003 H1013. doi: 10.1152/ajpheart.00803.2009
108. Dias-Peixoto MF, Santos RA, Gomes ER, Alves MN, Almeida PW, Greco L, Rosa M, Fauler B, Bader M, Alenina N, Guatimosim S, Molecular mechanisms involved in the angiotensin-(1-7)/Mas signaling pathway in cardiomyocytes. Hypertension 2008 52 542 548. doi: 10.1161/HYPERTENSIONAHA.108.114280
109. Patel SK, Velkoska E, Freeman M, Wai B, Lancefield TF, Burrell LM, From gene to protein-experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front Physiol 2014 5 227. doi: 10.3389/fphys.2014.00227
110. Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, Sandholm N, Thomas MC, Groop PH, FinnDiane Study Group FinnDiane Study Group Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens 2012 30 375 383. doi: 10.1097/HJH.0b013e32834f04b6
111. Díez-Freire C, Vázquez J, Correa de Adjounian MF, Ferrari MF, Yuan L, Silver X, Torres R, Raizada MK, ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol Genomics 2006 27 12 19. doi: 10.1152/physiolgenomics.00312.2005
112. Rentzsch B, Todiras M, Iliescu R, Popova E, Campos LA, Oliveira ML, Baltatu OC, Santos RA, Bader M, Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function. Hypertension 2008 52 967 973. doi: 10.1161/HYPERTENSIONAHA.108.114322
113. Yamazato M, Yamazato Y, Sun C, Diez-Freire C, Raizada MK, Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats. Hypertension 2007 49 926 931. doi: 10.1161/01.HYP.0000259942.38108.20
114. Te Riet L, Van Esch JH, Roks AJ, Van den Meiracker AH, Danser AH, Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res 2015 116 960 975. doi: 10.1161/CIRCRESAHA.116.303587
115. Gallagher PE, Ferrario CM, Tallant EA, Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol 2008 295 H2373 H2379. doi: 10.1152/ajpheart.00426.2008
116. Lieb W, Graf J, Götz A, König IR, Mayer B, Fischer M, Stritzke J, Hengstenberg C, Holmer SR, Döring A, Löwel H, Schunkert H, Erdmann J, Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy. J Mol Med (Berl) 2006 84 88 96. doi: 10.1007/s00109-005-0718-5
117. Yang W, Huang W, Su S, Li B, Zhao W, Chen S, Gu D, Association study of ACE2 (angiotensin I-converting enzyme 2) gene polymorphisms with coronary heart disease and myocardial infarction in a Chinese Han population. Clin Sci (Lond) 2006 111 333 340. doi: 10.1042/CS20060020
118. Keidar S, Strizevsky A, Raz A, Gamliel-Lazarovich A, ACE2 activity is increased in monocyte-derived macrophages from prehypertensive subjects. Nephrol Dial Transplant 2007 22 597 601. doi: 10.1093/ndt/gfl632
119. Bodiga S, Zhong JC, Wang W, Basu R, Lo J, Liu GC, Guo D, Holland SM, Scholey JW, Penninger JM, Kassiri Z, Oudit GY, Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47(phox) NADPH oxidase subunit. Cardiovasc Res 2011 91 151 161. doi: 10.1093/cvr/cvr036
120. Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, Tatara Y, Shiota A, Sugano S, Takeda S, Rakugi H, Ogihara T, Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension 2006 47 718 726. doi: 10.1161/01.HYP.0000205833.89478.5b
121. Tendera M, The epidemiology of heart failure. J Renin Angiotensin Aldosterone Syst 2004 5 suppl 1 S2 S6
122. Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, Tikellis C, Grant SL, Lew RA, Smith AI, Cooper ME, Johnston CI, Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J 2005 26 369 375; discussion 322. doi: 10.1093/eurheartj/ehi114
123. Kassiri Z, Zhong J, Guo D, Basu R, Wang X, Liu PP, Scholey JW, Penninger JM, Oudit GY, Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail 2009 2 446 455. doi: 10.1161/CIRCHEARTFAILURE.108.840124
124. Kim MA, Yang D, Kida K, Molotkova N, Yeo SJ, Varki N, Iwata M, Dalton ND, Peterson KL, Siems WE, Walther T, Cowling RT, Kjekshus J, Greenberg B, Effects of ACE2 inhibition in the post-myocardial infarction heart. J Card Fail 2010 16 777 785. doi: 10.1016/j.cardfail.2010.04.002
125. Der Sarkissian S, Grobe JL, Yuan L, Narielwala DR, Walter GA, Katovich MJ, Raizada MK, Cardiac overexpression of angiotensin converting enzyme 2 protects the heart from ischemia-induced pathophysiology. Hypertension 2008 51 712 718. doi: 10.1161/HYPERTENSIONAHA.107.100693
126. Qi Y, Shenoy V, Wong F, Li H, Afzal A, Mocco J, Sumners C, Raizada MK, Katovich MJ, Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia-induced cardiac pathophysiology. Exp Physiol 2011 96 863 874. doi: 10.1113/expphysiol.2011.056994
127. Zhao YX, Yin HQ, Yu QT, ACE2 overexpression ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction. Hum Gene Ther 2010 21 1545 1554. doi: 10.1089/hum.2009.160
128. Grobe JL, Der Sarkissian S, Stewart JM, Meszaros JG, Raizada MK, Katovich MJ, ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. Clin Sci (Lond) 2007 113 357 364. doi: 10.1042/CS20070160
129. Loot AE, Roks AJ, Henning RH, Tio RA, Suurmeijer AJ, Boomsma F, Van Gilst WH, Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation 2002 105 1548 1550
130. Huentelman MJ, Grobe JL, Vazquez J, Stewart JM, Mecca AP, Katovich MJ, Ferrario CM, Raizada MK, Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats. Exp Physiol 2005 90 783 790. doi: 10.1113/expphysiol.2005.031096
131. Qi Y, Zhang J, Cole-Jeffrey CT, Shenoy V, Espejo A, Hanna M, Song C, Pepine CJ, Katovich MJ, Raizada MK, Diminazene aceturate enhances angiotensin-converting enzyme 2 activity and attenuates ischemia-induced cardiac pathophysiology. Hypertension 2013 62 746 752. doi: 10.1161/HYPERTENSIONAHA.113.01337
132. Patel VB, Bodiga S, Basu R, Das SK, Wang W, Wang Z, Lo J, Grant MB, Zhong J, Kassiri Z, Oudit GY, Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis. Circ Res 2012 110 1322 1335. doi: 10.1161/CIRCRESAHA.112.268029
133. Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli N, Penninger JM, Grant MB, Lopaschuk GD, Oudit GY, ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity. Diabetes 2016 65 85 95. doi: 10.2337/db15-0399
134. Trask AJ, Groban L, Westwood BM, Varagic J, Ganten D, Gallagher PE, Chappell MC, Ferrario CM, Inhibition of angiotensin-converting enzyme 2 exacerbates cardiac hypertrophy and fibrosis in ren-2 hypertensive rats. Am J Hypertens 2010 23 687 693
135. Song B, Zhang ZZ, Zhong JC, Yu XY, Oudit GY, Jin HY, Lu L, Xu YL, Kassiri Z, Shen WF, Gao PJ, Zhu DL, Loss of angiotensin-converting enzyme 2 exacerbates myocardial injury via activation of the ctgf-fractalkine signaling pathway. Circ J 2013 77 2997 3006
136. Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL, Death in heart failure: a community perspective. Circ Heart Fail 2008 1 91 97. doi: 10.1161/CIRCHEARTFAILURE.107.743146
137. Alghamri MS, Weir NM, Anstadt MP, Elased KM, Gurley SB, Morris M, Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice. J Cardiovasc Pharmacol Ther 2013 18 138 151. doi: 10.1177/1074248412460124
138. Garabelli PJ, Modrall JG, Penninger JM, Ferrario CM, Chappell MC, Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart. Exp Physiol 2008 93 613 621. doi: 10.1113/expphysiol.2007.040246
139. Weber KT, Brilla CG, Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991 83 1849 1865
140. Dong B, Yu QT, Dai HY, Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy. J Am Coll Cardiol 2012 59 739 747. doi: 10.1016/j.jacc.2011.09.071
141. Oudit GY, Liu GC, Zhong J, Basu R, Chow FL, Zhou J, Loibner H, Janzek E, Schuster M, Penninger JM, Herzenberg AM, Kassiri Z, Scholey JW, Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes 2010 59 529 538. doi: 10.2337/db09-1218
142. Murça TM, Moraes PL, Capuruço CA, Santos SH, Melo MB, Santos RA, Shenoy V, Katovich MJ, Raizada MK, Ferreira AJ, Oral administration of an angiotensin-converting enzyme 2 activator ameliorates diabetes-induced cardiac dysfunction. Regul Pept 2012 177 107 115. doi: 10.1016/j.regpep.2012.05.093
143. Murça TM, Almeida TC, Raizada MK, Ferreira AJ, Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction. Exp Physiol 2012 97 699 709. doi: 10.1113/expphysiol.2011.063461
144. Yousif MH, Dhaunsi GS, Makki BM, Qabazard BA, Akhtar S, Benter IF, Characterization of Angiotensin-(1-7) effects on the cardiovascular system in an experimental model of type-1 diabetes. Pharmacol Res 2012 66 269 275. doi: 10.1016/j.phrs.2012.05.001
145. Mori J, Patel VB, Abo Alrob O, Basu R, Altamimi T, Desaulniers J, Wagg CS, Kassiri Z, Lopaschuk GD, Oudit GY, Angiotensin 1-7 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db/db mice by reducing lipotoxicity and inflammation. Circ Heart Fail 2014 7 327 339. doi: 10.1161/CIRCHEARTFAILURE.113.000672
146. Al-Maghrebi M, Benter IF, Diz DI, Endogenous angiotensin-(1-7) reduces cardiac ischemia-induced dysfunction in diabetic hypertensive rats. Pharmacol Res 2009 59 263 268. doi: 10.1016/j.phrs.2008.12.008
147. Basu R, Oudit GY, Wang X, Zhang L, Ussher JR, Lopaschuk GD, Kassiri Z, Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol 2009 297 H2096 H2108. doi: 10.1152/ajpheart.00452.2009
148. Tikellis C, Pickering R, Tsorotes D, Du XJ, Kiriazis H, Nguyen-Huu TP, Head GA, Cooper ME, Thomas MC, Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. Clin Sci (Lond) 2012 123 519 529. doi: 10.1042/CS20110668
149. Patel VB, Parajuli N, Oudit GY, Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications. Clin Sci (Lond) 2014 126 471 482. doi: 10.1042/CS20130344
150. Yancy CW, Jessup M, Bozkurt B, 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013 128 1810 1852. doi: 10.1161/CIR.0b013e31829e8807
151. Paulus WJ, Tschöpe C, A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013 62 263 271. doi: 10.1016/j.jacc.2013.02.092
152. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE, Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005 111 2605 2610. doi: 10.1161/CIRCULATIONAHA.104.510461
153. McMurray JJ, Pfeffer MA, Heart failure. Lancet 2005 365 1877 1889. doi: 10.1016/S0140-6736(05)66621-4
154. Poglitsch M, Domenig O, Schwager C, Stranner S, Peball B, Janzek E, Wagner B, Jungwirth H, Loibner H, Schuster M, Recombinant Expression and Characterization of Human and Murine ACE2: Species-Specific Activation of the Alternative Renin-Angiotensin-System. Int J Hypertens 2012 2012 428950. doi: 10.1155/2012/428950
155. Coutinho DC, Monnerat-Cahli G, Ferreira AJ, Medei E, Activation of angiotensin-converting enzyme 2 improves cardiac electrical changes in ventricular repolarization in streptozotocin-induced hyperglycaemic rats. Europace 2014 16 1689 1696. doi: 10.1093/europace/euu070
156. Haga S, Tsuchiya H, Hirai T, Hamano T, Mimori A, Ishizaka Y, A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression. Exp Lung Res 2015 41 21 31. doi: 10.3109/01902148.2014.959141
157. Shenoy V, Gjymishka A, Jarajapu YP, Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med 2013 187 648 657. doi: 10.1164/rccm.201205-0880OC
158. Shenoy V, Kwon KC, Rathinasabapathy A, Lin S, Jin G, Song C, Shil P, Nair A, Qi Y, Li Q, Francis J, Katovich MJ, Daniell H, Raizada MK, Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension. Hypertension 2014 64 1248 1259. doi: 10.1161/HYPERTENSIONAHA.114.03871
159. Caballero S, Sengupta N, Afzal A, Chang KH, Li Calzi S, Guberski DL, Kern TS, Grant MB, Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes 2007 56 960 967. doi: 10.2337/db06-1254
160. Jarajapu YP, Grant MB, The promise of cell-based therapies for diabetic complications: challenges and solutions. Circ Res 2010 106 854 869. doi: 10.1161/CIRCRESAHA.109.213140
161. Jarajapu YP, Bhatwadekar AD, Caballero S, Hazra S, Shenoy V, Medina R, Kent D, Stitt AW, Thut C, Finney EM, Raizada MK, Grant MB, Activation of the ACE2/angiotensin-(1-7)/Mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors. Diabetes 2013 62 1258 1269. doi: 10.2337/db12-0808