Angiotensin‐(1–7) administration benefits cardiac, renal and progenitor cell function in db/db mice

Abstract

Background and Purpose Diabetic patients are at an increased risk of cardiovascular disease, in part due to inflammation and oxidative stress. These two pathological mechanisms also affect other organs and cells including the kidneys and progenitor cells. Angiotensin‐(1–7) [Ang‐(1–7)] has previously been shown to counterbalance pathological effects of angiotensin II, including inflammation and oxidative stress. The aim of this study was to investigate the effects of short‐term (2 weeks) Ang‐(1–7) treatment on cardiovascular and renal function in a mouse model of type 2 diabetes (db/db). Experimental Approach Eight‐ to nine‐week‐old db/db mice were administered either vehicle, Ang‐(1–7) alone, or Ang‐(1–7) combined with an inhibitor (losartan, PD123319, A‐779, L‐NAME or icatibant) daily for 14 days. Key Results An improvement in physiological heart function was observed in Ang‐(1–7)‐treated mice. Ang‐(1–7) also reduced cardiomyocyte hypertrophy, fibrosis and inflammatory cell infiltration of the heart tissue and increased blood vessel number. These changes were blocked by antagonists of the MAS1, AT2 and bradykinin receptors and inhibition of NO formation. Treatment with Ang‐(1–7) reduced glomerular damage and oxidative stress in kidney tissue. Bone marrow and circulating endothelial progenitors, as well as bone marrow mesenchymal stem cells, were increased in mice treated with Ang‐(1–7). Conclusions and Implications Short‐term Ang‐(1–7) treatment of young db/db mice improved heart function and reduced kidney damage. Treatment also improved bone marrow and circulating levels of endothelial and mesenchymal stem cells. All of this may contribute to improved cardiovascular and renal function.

Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone pain

“…), Losartan potassium (0.4 mg/kg, i.p. ), PD 123319 (0.4 mg/kg, i.p), 44 vehicle (0.9% saline, i.p. ), or a combination of Ang-(1-7) and each antagonist.…”

Targeting Angiotensin-Converting Enzyme-2/Angiotensin-(1-7)/Mas Receptor Axis in the Vascular Progenitor Cells for Cardiovascular Diseases

“…Elegant studies have shown that bone marrow oxidative stress in mouse models of diabetes by Ang-(1-7) in diabetic bone marrow and increased levels of NO/cGMP levels (Mordwinkin et al, 2012;Papinska et al, 2015). CD34 cells derived from diabetic individuals have shown increased ROS levels that were normalized by Ang-(1-7), which was associated with increased NO levels (Jarajapu et al, 2013).…”

“…Similar findings were observed when dysfunctional diabetic cells were overexpressed with lentiviral ACE2 gene transfer in a mouse model of hindlimb ischemia . Pharmacological targeting of ACE2 or MasR has been proven to be successful in experimental models for diabetic wound healing and cardiopulmonary disorders, and the reparative end-points were associated with increased vascular regenerative capacity (Mordwinkin et al, 2012;Shenoy et al, 2013;Singh et al, 2014;Papinska et al, 2015;Vasam et al, 2017). Despite the shorter biological half-life, Ang-(1-7) administration has been shown to be effective even in nanomolar doses in a wide range of experimental models.…”

Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats

“…Additionally, an improvement in physiological heart function and cardiomyocyte hypertrophy was observed in Ang-(1–7)-treated mice (Papinska et al 2015). Alamandine is similar to Ang-(1–7) and differs only by the presence of an alanine residue in place of an aspartate residue at the amino end.…”