科研之友
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摘要
Background: Aldosterone and phospholipase C (PLC) stimulate nuclear factor-kappaB (NF-kappa B) and activating-protein (AP-1), causing fibrosis and hypertrophy. Besides harboring binding sites for NF-kappa B and AP-1, heme oxygenase (HO-1) generates cytoprotective products, including bilirubin and ferritin. The multifaceted interaction between HO-1 and aldosterone-PLC profibrotic axis in cardiac hypertrophy of spontaneously hypertensive rats (SHR) was studied. Methods and Results: HO-1 was induced with hemin or blocked with chromium mesoporphyrin (CrMP). The study groups included: (A) controls (SHR, WKY, and SD), (B) SHR hemin, (C) SHR hemin CrMP, (D) SHR CrMP, and (E) SHR vehicle. Histological and morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric assays were used to assess the effect of the HO system on cardiac hypertrophy. Hemin therapy evoked a 3-month enduring cardioprotection in adult SHR by lowering blood pressure, and reducing left-to-right ventricular ratio, left ventricular wall-thickness, and left ventricle-to-body-weight ratio, whereas CrMP exacerbated cardiac fibrosis/hypertrophy. The cardioprotection was accompanied by reduced aldosterone, PLC, inositol-triphosphate, NF-kappa B, AP-1, heme, and 8-isoprostane, a marker of oxidative stress, whereas HO-1, HO activity, cGMP, bilirubin, ferritin, superoxide dismutase, and the total antioxidant capacity were increased. Correspondingly, extracellular matrix/remodeling proteins such as fibronectin, collagen-1, collagen-IV, alongside cardiac histopathological lesions including fibrosis, scarring, muscular-hypertrophy, coronary-arteriolar thickening, and interstitial/perivascular collagen deposition were attenuated. Conclusions: Our study unveils sustained cardioprotection by hemin that may have clinical relevance. (J Cardiac Fail 2009;15:616-628)
- 出版日期2009-9
