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Simvastatin alleviates cardiac fibrosis induced by infarction via up‐regulation of TGF ‐β receptor III expression
Author(s) -
Sun Fei,
Duan Wenqi,
Zhang Yu,
Zhang Lingling,
Qile Muge,
Liu Zengyan,
Qiu Fang,
Zhao Dan,
Lu Yanjie,
Chu Wenfeng
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13166
Subject(s) - simvastatin , cardiac fibrosis , fibrosis , myocardial fibrosis , endocrinology , transforming growth factor , medicine , cardiac function curve , signal transduction , chemistry , biology , microbiology and biotechnology , heart failure
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.