Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 76, Issue -, Pages 148-157Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2014.08.008
Keywords
Pressure overload; Cardiac fibrosis; Cardiac fibroblasts; Glycoproteins; Heart failure
Categories
Funding
- University of Oslo, Oslo University Hospital [412234]
- Norwegian Council on Cardiovascular Disease [6604]
- KG Jebsen Cardiac Research Center and Center for Heart Failure Research, Raagholt Trust
- Blix Family Trust
- Rakel and Otto Bruun Trust
- Anders Jahre's Fund for the Promotion of Science
- South-Eastern Norway Regional Health Authority
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Pressure overload-induced TGF-beta signaling activates cardiac fibroblasts (CFB) and leads to increased extracellular matrix (ECM) protein synthesis including fibrosis. Excessive ECM accumulation may in turn affect cardiac function contributing to development of heart failure. The aim of this study was to examine the effects of SM16, an orally active small molecular inhibitor of ALK5, on pressure overload-induced cardiac fibrosis. One week after aortic banding (AB), C57B1/6J mice were randomized to standard chow or chow with SM16. Sham operated animals served as controls. Following 4 weeks AB, mice were characterized by echocardiography and cardiovascular magnetic resonance before sacrifice. SM16 abolished phosphorylation of SMAD2 induced by AB in vivo and by TGF-beta in CFB in vitro. Interestingly, Masson Trichrome and Picrosirius Red stained myocardial left ventricular tissue revealed reduced development of fibrosis and collagen cross-linking following AB in the SM16 treated group, which was confirmed by reduced hydroxyproline incorporation. Furthermore, treatment with SM16 attenuated mRNA expression following induction of AB in vivo and stimulation with TGF-beta in CFB in vitro of Coll a2, the cross-linking enzyme LOX, and the pro-fibrotic glycoproteins SPARC and osteopontin. Reduced ECM synthesis by CFB and a reduction in myocardial stiffness due to attenuated development of fibrosis and collagen cross-linking might have contributed to the improved diastolic function and cardiac output seen in vivo, in combination with reduced lung weight and ANP expression by treatment with SM16. Despite these beneficial effects on cardiac function and development of heart failure, mice treated with SM16 exhibited increased mortality, increased LV dilatation and inflammatory heart valve lesions that may limit the use of SM16 and possibly also other small molecular inhibitors of ALK5, as future therapeutic drugs. (c) 2014 Elsevier Ltd. All rights reserved.
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