Atorvastatin Attenuates Dehydromonocrotaline-induced Pulmonary Hypertension in Beagles in Early Stage
CHEN Dan-dan, QIAN Ju-ying, CHEN Fa-dong, GUAN Li-hua, YAO Rui-ming, DONG Li-li, YUAN Yong-gang, GE Jun-bo, ZHOU Da-xin.Department of Cardiology , Zhongshan Hospital of Fudan University ,Shanghai Cardiovascular Disease Institute ,Shanghai ,20032,China
Backgrounds: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by marked and sustained elevation of pulmonary hypertension. Atorvastatin which is a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor has been shown to attenuate chronic hypoxic pulmonary hypertension. Our study was to assess whether atorvastatin is capable of attenuating dehydromonocrotaline(DHMC)induced pulmonary hypertension in beagles and explore potential mechanisms of statin effect. Methods: DHMC was artificially synthesized as described by Mattocks and confirmed its structure and concentration using high performance liquid chromatography (HPLC). Our research was on eighteen 10-month-old beagles weighted 10~15kg, no sex limitation. We used the thermodilution method of hemodynamic measurements and arterial blood gases measured at baseline. Beagles were injected DHMC in on Day 1, and from Day 5 to 65 they received the therapy with Atorvastatin (2mg/kg, oral, every day , n=7), or vehicle(n=5),and the normal group(n=6). Two months later, the beagles underwent a hemodynamic evaluation with the thermodilution method followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Results: On Day 65, atorvastatin-treated beagles demonstrated lower mean pulmonary arterial pressure(mPAP) than vehicle-treated beagles(14.71±3.25mmHg versus 32.00±11.40mmHg, P0.05). Hematoxylin-eosin staining demonstrated less pulmonary endothelium reconstruction and smooth muscle cell proliferation in the atorvastatin-treated beagles. In addition, pulmonary preproET-1, VEGF, IL-1β, TNF-α RNA expressions were increased in vehicle-treated beagles but decreased toward normal levels in atorvastatin-treated group. eNOS mRNA was decreased in the vehicle-treated beagles but increased in the atorvastatin-treated group. Conclusions: Atorvastatin attenuates DHMC-induced pulmonary hypertension in beagles through inhibition of HMG-CoA reductase. Atorvastatin drugs inhibition of inflammatory cytokine expression, vasoactive substances and reversal of pulmonary vascular remodeling induced smooth muscle cell apoptosis may be an important mechanism of statin effect.
【Fund】： 上海市自然科学基金课题(07ZR14024);; “十一五”国家科技支撑计划重大项目(2006BAI01A07)资助
【CateGory Index】： R543.2
【CateGory Index】： R543.2