Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension

作者：Takenaka Hiroyuki; Kihara Yasuki^*; Iwanaga Yoshitaka; Onozawa Yoko; Toyokuni Shinya; Kita Toru

来源：Journal of Molecular and Cellular Cardiology, 2006, 41(6): 989-997.

DOI：10.1016/j.yjmcc.2006.07.019

• cardiac remodeling
• Angiotensin II
• extracellular matrix
• oxygen radicals
• NADPH oxidase
• NF kappa B
• matrix metalloproteinases

Angiotensin II (Ang-II) plays pivotal roles in the progression of left ventricular (LV) remodeling in diseased hearts; it remains to be elucidated how Ang-II links to degradation of the extracellular matrix (ECM). Using hypertensive Dahl salt-sensitive rats that show the distinctive transition from concentric LV hypertrophy to LV remodeling, we chronically treated them with an angiotensin type-1 receptor blocker (telmisartan 5 mg/kg/ day, ARB group) or vehicle (0.5% CMC, CHF group). During the process of LV remodeling, we assessed, (1) in-vivo LV shape and function; (2) animal survival; (3) amounts of ECM in LV using a scanning electron microscope (SEM); (4) mRNA (by real time RT-PCR) and protein (by immunoblotting) levels in LV of NADPH oxidase, glutathione peroxidase-1 (GPX-1), and matrix metalloproteinase (MMP)-2, -9, and -13; (5) immunohistochemical staining of myocardial 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine; (6) nuclear factor kappa-B (NF kappa B) protein levels in the nuclear extract; and (7) endogenous activities of MMP-2 and -9 by an antibody capture method. Compared with CHF, ARB group showed an improvement of survival and preserved LV shape and function, and ECM density in SEM that was accompanied by decreases in oxidative stress-mediated protein degenerations, activities of GPX-1, NADPH oxidase, NF kappa B, and MMP-2, -9, and -13. Local activation of Ang II in hypertrophic LV triggers MMP-mediated ECM degradation, namely LV remodeling, at least in part, through NADPH oxidase-induced oxidative stress and the subsequent NF kappa B activation.

• 出版日期2006-12