mln-4760 and Fibrosis

Emerging evidence suggests that cardiac angiotensin-converting enzyme 2 (ACE2) may contribute to the regulation of heart function and hypertension-induced cardiac remodeling. We tested the hypothesis that inhibition of ACE2 in the hearts of (mRen2)27 hypertensive rats may accelerate progression of cardiac hypertrophy and fibrosis by preventing conversion of angiotensin II (Ang II) into the antifibrotic peptide, angiotensin-(1-7) (Ang-(1-7)).. Fourteen male (mRen2)27 transgenic hypertensive rats (12 weeks old, 401 + or - 7 g) were administered either vehicle (0.9% saline) or the ACE2 inhibitor, MLN-4760 (30 mg/kg/day), subcutaneously via mini-osmotic pumps for 28 days.. Although ACE2 inhibition had no effect on average 24-h blood pressures, left ventricular (LV) Ang II content increased 24% in rats chronically treated with the ACE2 inhibitor (P < 0.05). Chronic ACE2 inhibition had no effect on plasma Ang II or Ang-(1-7) levels. Increased cardiac Ang II levels were associated with significant increases in both LV anterior, posterior, and relative wall thicknesses, as well as interstitial collagen fraction area and cardiomyocyte hypertrophy in the transgenic animals chronically treated with the ACE2 inhibitor. Cardiac remodeling was not accompanied by any further alterations in LV function.. These studies demonstrate that chronic inhibition of ACE2 causes an accumulation of cardiac Ang II, which exacerbates cardiac hypertrophy and fibrosis without having any further impact on blood pressure or cardiac function.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Fibrosis; Heart Ventricles; Imidazoles; Leucine; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Transgenic

Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme (ACE), converts angiotensin (Ang) I to Ang(1-9) and Ang II to Ang(1-7), but does not directly process Ang I to Ang II. Cardiac function is compromised in ACE2 null mice; however, the importance of ACE2 in the processing of angiotensin peptides within the murine heart is not known. We determined the metabolism of angiotensins in wild-type (WT), ACE (ACE(-/-)) and ACE2 null mice (ACE2(-/-)). Angiotensin II was converted almost exclusively to Ang(1-7) in the cardiac membranes of WT and ACE(-/-) strains, although generation of Ang(1-7) was greater in the ACE(-/-) mice (27.4 +/- 4.1 versus 17.5 +/- 3.2 nmol(-1) mg h(-1) for WT). The ACE2 inhibitor MLN4760 significantly attenuated Ang II metabolism and the subsequent formation of Ang(1-7) in both strains. In the ACE2(-/-) hearts, Ang II metabolism and the generation of Ang(1-7) were significantly attenuated; however, the ACE2 inhibitor reduced the residual Ang(1-7)-forming activity in this strain. Angiotensin I was primarily converted to Ang(1-9) (WT, 28.9 +/- 3.1 nmol(-1) mg h(-1); ACE(-/-), 49.8 +/- 5.3 nmol(-1) mg h(-1); and ACE2(-/-), 35.9 +/- 5.4 nmol(-1) mg h(-1)) and to smaller quantities of Ang(1-7) and Ang II. Although the ACE2 inhibitor had no effect on Ang(1-9) formation, the carboxypeptidase A inhibitor benzylsuccinate essentially abolished the formation of Ang(1-9) and increased the levels of Ang I in cardiac membranes. In conclusion, our studies in the murine heart suggest that ACE2 is the primary pathway for the metabolism of Ang II and the subsequent formation of Ang(1-7), a peptide that, in contrast to Ang II, exhibits both antifibrotic and antiproliferative actions.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Carboxypeptidases A; Cell Proliferation; Fibrosis; Heart; Imidazoles; Immunohistochemistry; Leucine; Male; Membranes; Mice; Mice, Knockout; Myocardium; Peptide Fragments; Peptidyl-Dipeptidase A; Protease Inhibitors; Succinates