Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats.

1. Metformin is an activator of AMP-activated protein kinase (AMPK). Recent studies suggest that pharmacological activation of AMPK inhibits cardiac hypertrophy. In the present study, we examined whether long-term treatment with metformin could attenuate ventricular hypertrophy in a rat model. The potential involvement of nitric oxide (NO) in the effects of metformin was also investigated. 2. Ventricular hypertrophy was established in rats by transaortic constriction (TAC). Starting 1 week after the TAC procedure, rats were treated with metformin (300 mg/kg per day, p.o.), N(G)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day, p.o.) or both for 8 weeks prior to the assessment of haemodynamic function and cardiac hypertrophy. 3. Cultured cardiomyocytes were used to examine the effects of metformin on the AMPK-endothelial NO synthase (eNOS) pathway. Cells were exposed to angiotensin (Ang) II (10⁻6 mol/L) for 24 h under serum-free conditions in the presence or absence of metformin (10⁻³ mol/L), compound C (10⁻6 mol/L), L-NAME (10⁻6 mol/L) or their combination. The rate of incorporation of [³H]-leucine was determined, western blotting analyses of AMPK-eNOS, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) were undertaken and the concentration of NO in culture media was determined. 4. Transaortic constriction resulted in significant haemodynamic dysfunction and ventricular hypertrophy. Myocardial fibrosis was also evident. Treatment with metformin improved haemodynamic function and significantly attenuated ventricular hypertrophy. Most of the effects of metformin were abolished by concomitant L-NAME treatment. L-NAME on its own had no effect on haemodynamic function and ventricular hypertrophy in TAC rats. 5. In cardiomyocytes, metformin inhibited AngII-induced protein synthesis, an effect that was suppressed by the AMPK inhibitor compound C or the eNOS inhibitor L-NAME. The improvement in cardiac structure and function following metformin treatment was associated with enhanced phosphorylation of AMPK and eNOS and increased NO production. 6. The findings of the present study indicate that long-term treatment with metformin could attenuate ventricular hypertrophy induced by pressure overload via activation of AMPK and a downstream signalling pathway involving eNOS-NO.

[Association between hemoglobin scavenger receptor CD163 expression and coronary atherosclerotic severity in patients with coronary heart disease].

OBJECTIVE: To investigate the association between hemoglobin scavenger receptor (CD163) expression levels on monocytic surfaces and coronary atherosclerotic severity in patients with coronary heart disease (CHD) as well as the roles of CD163 in inflammation and lipidperoxidation. METHODS: Eighty-four patients were diagnosed as CHD according to the results of coronary angiography and ACC/AHA diagnostic criteria. The patients were divided into 3 groups: acute myocardial infarction (AMI) group (n = 30), unstable angina (UA) group (n = 30), stable angina (SA) group (n = 24). Another 20 patients with normal coronary artery served as control. Expression levels of CD163 on monocytes were detected by means of flow cytometry, and the results were shown as mean fluorescence intensity (mfi). All patients underwent coronary angiography and the results were further evaluated by Jenkins score. Serum CRP and LDL-C were also measured. RESULTS: The expression levels of CD163 on monocytes in peripheral blood were significantly higher in CHD patients compared to controls (P < 0.01) in the order of AMI group [(84.4 +/- 6.9) mfi] > UA group [(64.1 +/- 5.5) mfi, P < 0.01 vs. AMI] > SA group [(46.7 +/- 6.5) mfi, P < 0.01 vs. AMI and UA] > control group [(22.0 +/- 6.1) mfi, P < 0.01 vs. AMI, UA and SA]. The expression levels of CD163 on monocytes in patients with CHD were positively correlated with Jenkins score (r = 0.9107, P < 0.01), CRP (r = 0.766, P < 0.01) and LDL-C (r = 0.749, P < 0.01). CONCLUSIONS: Expression levels of CD163 was significantly increased in patients with CHD and positively correlated with coronary heart disease severity and serum CRP and LDL-C.