An advanced endothelial murine HFpEF model: eNOS is critical for angiotensin 1–7 rescue of the diabetic phenotype

Diabetes and obesity are hallmark clinical features of patients with heart failure with preserved ejection fraction (HFpEF). [ [1] Shah S.J. Borlaug B.A. Kitzman D.W. McCulloch A.D. Blaxall B.C. Agarwal R. Chirinos J.A. Collins S. Deo R.C. Gladwin M.T. Granzier H. Hummel S.L. Kass D.A. Redfield M.M. Sam F. Wang T.J. Desvigne-Nickens P. Adhikari B.B. Research priorities for heart failure with preserved ejection fraction: National Heart, Lung, and Blood Institute Working Group Summary. Circulation. 2020; 141: 1001-1026 Crossref PubMed Scopus (137) Google Scholar , [2] Ter Maaten J.M. Damman K. Verhaar M.C. Paulus W.J. Duncker D.J. Cheng C. van Heerebeek L. Hillege H.L. Lam C.S. Navis G. Voors A.A. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur. J. Heart Fail. 2016; 18: 588-598 Crossref PubMed Scopus (188) Google Scholar ] Activation of the renin-angiotensin system (RAS) can exacerbate HFpEF and is a primary cause of cardiorenal and vascular injury in patients living with different forms of metabolic syndrome. [ [1] Shah S.J. Borlaug B.A. Kitzman D.W. McCulloch A.D. Blaxall B.C. Agarwal R. Chirinos J.A. Collins S. Deo R.C. Gladwin M.T. Granzier H. Hummel S.L. Kass D.A. Redfield M.M. Sam F. Wang T.J. Desvigne-Nickens P. Adhikari B.B. Research priorities for heart failure with preserved ejection fraction: National Heart, Lung, and Blood Institute Working Group Summary. Circulation. 2020; 141: 1001-1026 Crossref PubMed Scopus (137) Google Scholar , [2] Ter Maaten J.M. Damman K. Verhaar M.C. Paulus W.J. Duncker D.J. Cheng C. van Heerebeek L. Hillege H.L. Lam C.S. Navis G. Voors A.A. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur. J. Heart Fail. 2016; 18: 588-598 Crossref PubMed Scopus (188) Google Scholar ] Heightened Ang II signaling drives cardiorenal maladaptation in diabetic pathological states. [ [1] Shah S.J. Borlaug B.A. Kitzman D.W. McCulloch A.D. Blaxall B.C. Agarwal R. Chirinos J.A. Collins S. Deo R.C. Gladwin M.T. Granzier H. Hummel S.L. Kass D.A. Redfield M.M. Sam F. Wang T.J. Desvigne-Nickens P. Adhikari B.B. Research priorities for heart failure with preserved ejection fraction: National Heart, Lung, and Blood Institute Working Group Summary. Circulation. 2020; 141: 1001-1026 Crossref PubMed Scopus (137) Google Scholar , [3] Wang K. Gheblawi M. Nikhanj A. Munan M. MacIntyre E. O’Neil C. Poglitsch M. Colombo D. Del Nonno F. Kassiri Z. Sligl W. Oudit G.Y. Dysregulation of ACE (angiotensin-converting enzyme)-2 and renin-angiotensin peptides in SARS-CoV-2 mediated mortality and end-organ injuries. Hypertension. 2022; 79: 365-378 Crossref PubMed Scopus (17) Google Scholar , [4] Patel V.B. Zhong J.C. Grant M.B. Oudit G.Y. Role of the ACE2/angiotensin 1-7 Axis of the renin-angiotensin system in heart failure. Circ. Res. 2016; 118: 1313-1326 Crossref PubMed Scopus (496) Google Scholar ] Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1‐–7, offering an endogenous counterregulatory RAS axis which is frequently dysregulated in diseased states. [ [4] Patel V.B. Zhong J.C. Grant M.B. Oudit G.Y. Role of the ACE2/angiotensin 1-7 Axis of the renin-angiotensin system in heart failure. Circ. Res. 2016; 118: 1313-1326 Crossref PubMed Scopus (496) Google Scholar , [5] Viveiros A. Gheblawi M. Aujla P.K. Sosnowski D.K. Seubert J.M. Kassiri Z. Oudit G.Y. Sex- and age-specific regulation of ACE2: insights into severe COVID-19 susceptibility. J. Mol. Cell. Cardiol. 2022; 164: 13-16 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar ] Ang 1‐–7/ACE2 axis has been proposed as a novel therapy for HFpEF. [ [4] Patel V.B. Zhong J.C. Grant M.B. Oudit G.Y. Role of the ACE2/angiotensin 1-7 Axis of the renin-angiotensin system in heart failure. Circ. Res. 2016; 118: 1313-1326 Crossref PubMed Scopus (496) Google Scholar ]