Simvastatin alleviates cardiac fibrosis induced by infarction via up‐regulation of TGF ‐β receptor III expression

Background and Purpose Statins decrease heart disease risk, but their mechanisms are not completely understood. We examined the role of the TGF ‐β receptor III ( TGFBR 3) in the inhibition of cardiac fibrosis by simvastatin. Experimental Approach Myocardial infarction ( MI ) was induced by ligation of the left anterior descending coronary artery in mice given simvastatin orally for 7 days. Cardiac fibrosis was measured by M asson staining and electron microscopy. Heart function was evaluated by echocardiography. Signalling through TGFBR 3, ERK 1/2, JNK and p38 pathways was measured using Western blotting. Collagen content and cell viability were measured in cultures of neonatal mouse cardiac fibroblasts ( NMCFs ). Interactions between TGFBR 3 and the scaffolding protein, GAIP ‐interacting protein C ‐terminus ( GIPC ) were detected using co‐immunoprecipitation (co‐ IP ). In vivo , hearts were injected with lentivirus carrying shRNA for TGFBR 3. Key Results Simvastatin prevented fibrosis following MI , improved heart ultrastructure and function, up‐regulated TGFBR 3 and decreased ERK 1/2 and JNK phosphorylation. Simvastatin up‐regulated TGFBR 3 in NMCFs , whereas silencing TGFBR 3 reversed inhibitory effects of simvastatin on cell proliferation and collagen production. Simvastatin inhibited ERK 1/2 and JNK signalling while silencing TGFBR 3 opposed this effect. Co‐ IP demonstrated TGFBR 3 binding to GIPC . Overexpressing TGFBR 3 inhibited ERK 1/2 and JNK signalling which was abolished by knock‐down of GIPC . In vivo , suppression of cardiac TGFBR 3 abolished anti‐fibrotic effects, improvement of cardiac function and changes in related proteins after simvastatin. Conclusions and Implications TGFBR 3 mediated the decreased cardiac fibrosis, collagen deposition and fibroblast activity, induced by simvastatin, following MI . These effects involved GIPC inhibition of the ERK 1/2/ JNK pathway.