Mechanisms And Effects Of Atorvastatin On Monocrotaline-induced Pulmonary Arterial Hypertension In Rats By~1NMR-based Metabonomic Analysis

Metabolomics based on nuclear magnetic resonance (NMR) is a combines the1HNMR spectroscopic detection with pattern recognition technologies. It can be used forexplaining the pharmacodynamic action, toxicological assessment and the mechanism.It can also be used for explaining the pathogenesis, screening biomarker and earlydiagnosis. In the basicscientific research，the metabolomics based on NMR was usedfor exploring the metabolism of monocrotaline-induced pulmonary hypertension inrats and the underlying molecular mechanisms of atorvastatin. This theme consists ofthree parts as follows：Part I Study the changes of metabolism based NMR in rats with pulmonary arterialhypertension induced by monocrotaline. The rats were divided into two groups：control rats (Ctr) and rats of PAH induced by MCT (PAH).The mean pulmonaryarterial pressure(MPAP)，the index of right ventricular hypertrophy and microstructureof pulmonary artery were detected, and the samples of serum were detected by thehydrogen spectrum of the serum NMR. It was found that PAH was establishedsuccessfully by MCT. The remodeling of pulmonary vascular appeared in the2ndweek and the pulmonary hypertension developed in the3rd week. The differentmetabolic patterns such as stress, cell damage, repairing for damaged tissue, the fattyacid β-oxidation and the Warburg effect in rats were found at different time pointsafter the injection of monocrotaline. The pulmonary artery reconstruction in rat wasclosely related with the fatty acid β-oxidation and the Warburg effect in2nd weekand3rd week. The increasing of carnitine, β-hydroxybutyric acid, citric acid and thedecline of acetic acid, acetone would be as parametesr of deterioration of pathologicalchange in PAH rats.Part II Study on the changes of metabolism based NMR in rats with pulmonaryhypertension treated by atorvastatin. PAH rats treated with atorvastatin(Ato).Themean pulmonary arterial pressure(MPAP)，the index of right ventricular hypertrophyand microstructure of pulmonary artery were detected, and the samples of serum were detected by the hydrogen spectrum of the serum NMR.The pulmonary vascularremodeling was improved significantly by atorvastatin. The inhibition of fatty acidβ-oxidation and and the Warburg effect were closely related with atorvastatin.Part Ⅲ Study on the molecular mechanism of metabolic changes in rats withpulmonary hypertension model of atorvastatin on monocrotaline induced. Theexpression of both mRNA and protein of GSK-3β，SERBP-1c，hexokinase，and theCPT-1in the rats were measured by RT-PCR and Western-Blot in all three groups.First, it was found that expression of GSK-3β was decreased and hexokinase wasactivatied after the injection of MCT. Second, the expression of sterol regulatoryelement binding protein was decreased as well as the activation of CPT-1and theenhancement of fatty acid oxidation. Third, the decreased expression of GSK-3βwould be inhibited by atorvastatin inhibiting hexokinase. Atorvastatin also activatedthe sterol regulatory element binding protein, then inhibited CPT-1, and thendecreased fatty acid oxidation.