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Cardiac diastolic dysfunction has emerged as a growing type of heart failure. The present study aims to explore whether Qiliqiangxin (QL) can benefit cardiac diastolic function in spontaneously hypertensive rats (SHRs) through enhancement of cardiac glucose metabolism.
Fifteen 12-month-old male SHRs were randomly divided into QL-treated (0.5g/kg·d), olmesartan-treated (2.5mg/kg·d) and saline-treated groups. Age-matched WKY rats served as normal controls. Systolic blood pressure and echocardiographic evaluation were carried out before and 8 weeks after drug administration. Myocardial glucose uptake was determined by 18F-FDG using small-animal positron emission tomography (PET) imaging with standardized uptake value (SUV) calculated. After euthanasia, plasma NT-proBNP, TNF-α, TGF-β1 and histopathological changes were assessed. Protein expressions of GLUT-1, GLUT-4, phospho-AMPKα, PGC-1α, together with myocardial ATP content and citrate synthase (CS) activity were evaluated. Gene expressions of hexokinase-2 (HK2), pyruvate dehydrogenase kinase-4 (PDK4) and CS were also detected.
SHRs exhibited left ventricular diastolic dysfunction, cardiac hypertrophy, fibrosis and apoptosis, and impaired myocardial glucose metabolism compared with WKY rats. QL improved cardiac diastolic function, as evidenced by increased E’/A’ (1.21±0.16 vs. 0.87±0.17, p<0.01) and decreased E/E’ (23.43±2.23 vs. 31.30±4.23, p<0.01), which were independent of systolic blood pressure. QL significantly decreased plasma levels of NT-proBNP (192.3±42.5pg/ml vs. 337.8±64.9pg/ml, p<0.01), TNF-α (72.9±7.4pg/ml vs. 86.8±8.9pg/ml, p<0.05) and TGF-β1 (19.4±2.6ng/ml vs. 23.3±3.5 ng/ml, p<0.01), which were markedly higher in saline-treated SHRs. Meanwhile, QL alleviated myocardial hypertrophy, collagen deposits and apoptosis in SHRs, as exhibited by decreased cardiomyocyte cross-sectional area (613.4±66.8μm2 vs. 760.6±63.3μm2, p<0.01), reduced percentage of fibrotic deposits(6.96±0.77% vs. 12.70±1.38%, p<0.01), and fewer TUNEL positive cells(13.76±2.31 vs. 23.30±5.94, p<0.01). Compared with age-matched WKY rats, PET acquisition showed an increase in myocardial 18F-FDG uptake in SHRs(4.94±0.51 vs. 2.94±0.39, p<0.01); while an even higher myocardial glucose uptake was illustrated in QL-treated SHR group (7.10±0.72 vs. 4.94±0.51, p<0.01). Moreover, QL-treated animals revealed a significantly higher myocardial CS activity (1307.7±125.5nmol/min/mg vs. 932.5±69.5nmol/min/mg, p<0.05) and ATP production (26.8±2.9 μmol/mg vs. 17.3±4.0 μmol/mg, p<0.01) than SHR control. Western blotting exhibited a significantly increased GLUT-4, phospho-AMPKαThr172, PGC-1α and decreased GLUT-1 expression in QL-treated SHRs in comparison to SHR control (p<0.01). qRT-PCR results showed that QL significantly upregulated mRNA expressions of HK2 and CS, and downregulated PDK4 expression (p<0.01). Olmesartan also demonstrated beneficial effects on cardiac diastolic function and glucose metabolism.
Our data suggests that QL improves cardiac diastolic function and inhibits myocardial hypertrophy, fibrosis and apoptosis in SHRs, which may be associated with enhancement of myocardial glucose uptake, utilization and oxidative phosphorylation.