Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction. (1st April 2014)

• Record Type: Journal Article
• Authors: Fan, Dong; Takawale, Abhijit; Basu, Ratnadeep; Patel, Vaibhav; Lee, Jiwon; Kandalam, Vijay; Wang, Xiuhua; Oudit, Gavin Y.; Kassiri, Zamaneh
• Is Part Of: Cardiovascular research. Volume 103:Number 2(2014)
• Page Start: 268
• Page End: 280
• Publication Date: 2014-04-01
• Subjects: Tissue inhibitor of metalloproteinase -- Hypertrophy -- Fibrosis -- Diastolic dysfunction -- Extracellular matrix -- Matricellular proteins -- Cardiac fibroblast; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu072
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Tissue inhibitor of metalloproteinases (TIMPs) can mediate myocardial remodelling, hypertrophy, and fibrosis in heart disease. We investigated the impact of TIMP2 vs. TIMP3 deficiency in angiotensin II (Ang II)-induced myocardial remodelling and cardiac dysfunction. Methods and results: TIMP2 −/−, TIMP3 −/−, and wild-type (WT) mice received Ang II/saline (Alzet pump) for 2 weeks. Ang II infusion resulted in enhanced myocardial hypertrophy and lack of fibrosis in TIMP2 −/−, and conversely, excess fibrosis without hypertrophy in TIMP3 −/− mice. Echocardiographic imaging revealed preserved ejection fraction in all groups; however, exacerbated left ventricular (LV) diastolic dysfunction was detected in Ang II-infused TIMP2 −/− and TIMP3 −/− mice, despite the suppressed Ang II-induced hypertension in TIMP3 −/− mice. Enhanced hypertrophy in TIMP2 −/− mice impaired active relaxation, while excess fibrosis in TIMP3 −/− mice increased LV passive stiffness. Adult WT cardiomyocytes, only when co-cultured with cardiac fibroblasts, exhibited Ang II-induced hypertrophy which was suppressed in TIMP3 −/− cardiomyocytes. In vitro studies on adult cardiofibroblasts (quiescent and cyclically stretched), and in vivo analyses, revealed that the increased fibrosis in TIMP3 −/− -Ang II hearts is due to post-translational stabilization and deposition of collagen by matricellular proteins [osteopontin and Secreted Protein Acidic and Rich in Cysteine (SPARC)], which correlated with increased inflammation, rather than increased de novo synthesis. Reduced cross-linking enzymes, LOX and PLOD1, could underlie suppressed collagen deposition in TIMP2 −/− -Ang II hearts. Conclusion: TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function. TIMP2 −/− and TIMP3 −/− mice provide a unique opportunity to study myocardial hypertrophy and fibrosis independently, and their impact on cardiac dysfunction.