Effects of Direct Renin Inhibition on Myocardial Fibrosis and Cardiac Fibroblast Function

Abstract

Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function.

Biochemical and histological impact of direct renin inhibition by aliskiren on myofibroblasts activation and differentiation in bleomycin induced pulmonary fibrosis in adult mice

“…However Montes et al (2012) found that renin was able to induce the up-regulation of profibrotic molecules through an Ang II-independent pathway, since inhibition of Ang II by losartan or of angiotensin converting enzyme by captopril had a minimal or no effect on the renin-induced up-regulation of the fibrotic mediators TGF-␤1 and collagen. In other conditions as in non-hypertrophic mouse model of myocardial fibrosis, aliskiren prevented collagen deposition by cardiac fibroblasts (Zhi et al, 2013). This may explain the decrease in the myofibroblasts as detected by ␣SMA noticed in group IV of the current study.…”

Intermedin_1–53 Protects Against Myocardial Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Inflammation Induced by Homocysteine in Apolipoprotein E-Deficient Mice

“…Then the medium, which mostly contained cardiomyocytes, was decanted, and the purified CFs were cultured in fresh DMEM containing 10% FBS. Before reagent treatment, cells were starved with serum-free medium for 24 h. After incubation with IMD 1–53 (10 −7 m ol/L) for 30 min, CFs were stimulated with Hcy (2 × 10 −4 m ol/L) for 24 h as described 12) .…”

“…Plasma Hcy level was closely relative to left ventricular myocardial hypertrophy and left ventricle mass fraction 8, 9) . In addition, Hcy led to several heart morphological alterations including myocardial fibrosis and myocardial hypertrophy in vivo and in vitro 7, 10–12) .…”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…In vitro, all components of the RAAS activate cardiac fibroblasts. Renin directly induces a pro-fibrotic program in cardiac fibroblasts (63). Angiotensin II activates AT1 receptors stimulating cardiac fibroblast proliferation and enhancing matrix protein synthesis (64), (65), (66).…”

“…Aldosterone enhances proliferation (69) and potently stimulates matrix protein synthesis in cardiac fibroblasts, while activating fibrogenic signaling in cardiomyocytes (70) and macrophages (71). In vivo, renin inhibition, ACE inhibition, AT1 blockade and aldosterone antagonism attenuate interstitial fibrosis in experimental models of myocardial infarction and of cardiac remodeling induced by pressure overload (72), (73), (74), (63), (75). …”