Tsuruda Toshihiro, Costello-Boerrigter Lisa C, Burnett John C
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Heart Fail Rev. 2004 Jan;9(1):53-61. doi: 10.1023/B:HREV.0000011394.34355.bb.
Regulation of the extracellular matrix (ECM) is an important therapeutic target that can potentially attenuate the adverse ventricular remodeling seen in the progression of heart failure. Matrix metalloproteinases (MMPs) degrade numerous ECM proteins. Importantly, the activation of MMPs and their endogenous inhibitors (TIMPs) are associated with ventricular remodeling. Bioactive-molecules (vasoactive peptides) become activated in proportion to the magnitude of heart failure and have been demonstrated to affect directly collagen degradation as well as collagen synthesis in the myocardium. Pro-fibrotic factors such as norepinephrine, angiotensin II, and endothelin-1 stimulate fibrosis by modulating collagen synthesis and MMP/TIMP activity. Antagonism of these bioactive-molecules has produced improved hemodynamic performance concomitant with modulation of MMP/TIMP activity and in association with reverse remodeling. The natriuretic peptides and nitric oxide, both of which function via the second messenger cGMP, demonstrate anti-fibrotic actions by inhibiting collagen synthesis and by stimulating MMP activity. Furthermore, bioactive-molecules along with certain cytokines are reported to amplify MMP activity, suggesting that different signaling systems work together to modulate ECM turnover. Taken together, the evidence supports an important functional role for bioactive-molecules in the regulation of ECM turnover and suggests that pharmacological intervention at the level of such bioactive molecules may provide potential therapeutic strategies for attenuation of the adverse ventricular remodeling associated with the progression of heart failure.
细胞外基质（ECM）的调节是一个重要的治疗靶点，它有可能减轻心力衰竭进展过程中出现的不良心室重塑。基质金属蛋白酶（MMPs）可降解多种ECM蛋白。重要的是，MMPs及其内源性抑制剂（TIMPs）的激活与心室重塑有关。生物活性分子（血管活性肽）会随着心力衰竭的严重程度而被激活，并且已被证明会直接影响心肌中的胶原蛋白降解以及胶原蛋白合成。去甲肾上腺素、血管紧张素II和内皮素-1等促纤维化因子通过调节胶原蛋白合成和MMP/TIMP活性来刺激纤维化。拮抗这些生物活性分子可改善血流动力学性能，同时调节MMP/TIMP活性并与逆向重塑相关。利钠肽和一氧化氮均通过第二信使环磷酸鸟苷（cGMP）发挥作用，它们通过抑制胶原蛋白合成和刺激MMP活性来显示抗纤维化作用。此外，据报道生物活性分子与某些细胞因子一起可增强MMP活性，这表明不同的信号系统共同作用来调节ECM周转。综上所述，证据支持生物活性分子在ECM周转调节中具有重要的功能作用，并表明在此类生物活性分子水平上进行药物干预可能为减轻与心力衰竭进展相关的不良心室重塑提供潜在的治疗策略。
