Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction

被引：109

作者：

Fan, Dong ^{[1
,2
]}

Takawale, Abhijit ^{[1
,2
]}

Basu, Ratnadeep ^{[1
,2
]}

Patel, Vaibhav ^{[2
,3
]}

Lee, Jiwon ^{[1
,2
]}

Kandalam, Vijay ^{[1
,2
]}

Wang, Xiuhua ^{[1
,2
]}

Oudit, Gavin Y. ^{[2
,3
]}

Kassiri, Zamaneh ^{[1
,2
]}

机构：

[1] Univ Alberta, Dept Physiol, Edmonton, AB, Canada

[2] Univ Alberta, Mazankowski Alberta Heart Inst, Cardiovasc Res Ctr, Edmonton, AB, Canada

[3] Univ Alberta, Dept Med, Div Cardiol, Edmonton, AB, Canada

来源：

CARDIOVASCULAR RESEARCH | 2014年 / 103卷 / 02期

关键词：

Tissue inhibitor of metalloproteinase; Hypertrophy; Fibrosis; Diastolic dysfunction; Extracellular matrix; Matricellular proteins; Cardiac fibroblast; PRESERVED EJECTION FRACTION; SPARC-NULL MICE; HEART-FAILURE; PRESSURE-OVERLOAD; ANGIOTENSIN-II; MYOCARDIAL-INFARCTION; EXTRACELLULAR-MATRIX; TISSUE INHIBITOR; BIOMECHANICAL STRESS; COLLAGEN ACCUMULATION;

D O I：

10.1093/cvr/cvu072

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 2weeks. 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.

引用

页码：268 / 280

页数：13

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