Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute.
Cardiovascular research Centre, Mazankowski Alberta Heart Institute Department of Medicine/Division of Cardiology, University of Alberta, Edmonton AB, Canada.
Cardiovasc Res. 2014 Jul 15;103(2):268-80. doi: 10.1093/cvr/cvu072. Epub 2014 Apr 1.
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.
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.
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.
金属蛋白酶组织抑制剂 (TIMP) 可介导心脏病中的心肌重构、肥大和纤维化。我们研究了 TIMP2 与 TIMP3 缺乏对血管紧张素 II (Ang II) 诱导的心肌重构和心功能障碍的影响。
TIMP2(-/-)、TIMP3(-/-)和野生型 (WT) 小鼠接受 Ang II/盐水 (Alzet 泵) 输注 2 周。Ang II 输注导致 TIMP2(-/-)小鼠心肌肥大增强而纤维化缺乏，相反，TIMP3(-/-)小鼠则出现无肥大的过度纤维化。超声心动图成像显示所有组的射血分数均保留；然而，在 Ang II 输注的 TIMP2(-/-)和 TIMP3(-/-)小鼠中检测到左心室 (LV) 舒张功能障碍加重，尽管 TIMP3(-/-)小鼠中的 Ang II 诱导性高血压受到抑制。TIMP2(-/-)小鼠的增强肥大损害了主动松弛，而 TIMP3(-/-)小鼠的过度纤维化增加了 LV 被动僵硬度。仅当与心肌成纤维细胞共培养时，成年 WT 心肌细胞才会表现出 Ang II 诱导的肥大，而在 TIMP3(-/-)心肌细胞中这种肥大受到抑制。对成年心肌成纤维细胞 (静止和周期性拉伸) 的体外研究以及体内分析表明，TIMP3(-/-)-Ang II 心脏中的纤维化增加是由于基质细胞蛋白 [骨桥蛋白和富含半胱氨酸的酸性分泌蛋白 (SPARC)] 的翻译后稳定和沉积导致的，这与炎症增加相关，而不是新的胶原蛋白合成增加。交联酶 LOX 和 PLOD1 的减少可能是 TIMP2(-/-)-Ang II 心脏中胶原沉积减少的原因。
TIMP2 和 TIMP3 在心梗病理重塑中发挥基本且不同的作用，独立于其 MMP 抑制功能。TIMP2(-/-)和 TIMP3(-/-)小鼠为研究心肌肥大和纤维化提供了独特的机会，并且研究了它们对心功能障碍的影响。
