Qiliqiangxin Enhances Cardiac Glucose Metabolism and Improves Diastolic Function in Spontaneously Hypertensive Rats

Abstract

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 rat (SHR) through enhancement of cardiac glucose metabolism. Fifteen 12-month-old male SHRs were randomly divided into QL-treated, olmesartan-treated, and saline-treated groups. Age-matched WKY rats served as normal controls. Echocardiography and histological analysis were performed. Myocardial glucose uptake was determined by ¹⁸F-FDG using small-animal PET imaging. Expressions of several crucial proteins and key enzymes related to glucose metabolism were also evaluated. As a result, QL improved cardiac diastolic function in SHRs, as evidenced by increased E'/A'and decreased E/E' (P < 0.01). Meanwhile, QL alleviated myocardial hypertrophy, collagen deposits, and apoptosis (P < 0.01). An even higher myocardial glucose uptake was illustrated in QL-treated SHR group (P < 0.01). Moreover, an increased CS activity and ATP production was observed in QL-treated SHRs (P < 0.05). QL enhanced cardiac glucose utilization and oxidative phosphorylation in SHRs by upregulating AMPK/PGC-1α axis, promoting GLUT-4 expression, and regulating key enzymes related to glucose aerobic oxidation such as HK2, PDK4, and CS (P < 0.01). Our data suggests that QL improves cardiac diastolic function in SHRs, which may be associated with enhancement of myocardial glucose metabolism.

Figure 1

Left ventricular diastolic function assessed by transmitral pulsed-wave Doppler imaging and tissue Doppler imaging at the level of lateral mitral annulus from apical 4-chamber view. Maximal flow velocities of the early (E)/late (A) waves and maximal tissue velocity of early (E′)/late (A′) diastolic waves were recorded correspondingly. QL improved diastolic function in SHR, as illustrated by increased E′/A′ ratio instead of E/A ratio.

Figure 2

Left ventricular mass index (LVMI) and plasma levels of NT-proBNP, TNF-α, and TGF-β1 shown in all the four groups. Olm, olmesartan; ^∗P < 0.05 versus WKY + saline group; ^∗∗P < 0.01 versus WKY + saline group; ^#P < 0.05 versus SHR + saline group; ^##P < 0.01 versus SHR + saline group.

Figure 3

Photography of HE staining (400x), Masson's trichrome staining (200x), and TUNEL staining (400x) for assessment of cardiomyocyte cross-sectional area (CSA), percentage of fibrosis area, and cardiomyocyte apoptosis, respectively. Olm, olmesartan; ^∗∗P < 0.01 versus WKY + saline group; ^##P < 0.01 versus SHR + saline group.

Figure 4

Representative transverse, sagittal, and coronal positron emission tomography (PET) images for myocardial ¹⁸F-FDG uptake from the four groups of animals were shown. ¹⁸F-FDG uptake, expressed as standardized uptake value (SUV), was higher in SHRs than in WKY rats. An even higher ¹⁸F-FDG uptake was noted in SHR + QL group. Olm, olmesartan; ^∗∗P < 0.01 versus WKY + saline group; ^##P < 0.01 versus SHR + saline group.

Figure 5

Mitochondrial function, along with relevant protein and gene expressions in the heart of experimental animals. (a) Relative protein expressions including GLUT-1, GLUT-4, PGC-1α, and p-AMPKα in left ventricular myocardium of the four animal groups. GLUT-1, glucose transporter-1; GLUT-4, glucose transporter-4; PGC-1α, peroxisome proliferator-activated receptor coactivator-1α; p-AMPKα, phospho-AMP-activated protein kinase α. (b) Citrate synthase activity measured in heart homogenates and expressed as nmol/min per milligram of total protein. (c) ATP concentration detected in LV myocardial tissues of the four animal groups. (d) Relative HK2, PDK4, and CS mRNA expressions in left ventricular myocardium of the four animal groups. HK2, hexokinase-2; PDK4, pyruvate dehydrogenase kinase-4; CS, citrate synthase. Olm, olmesartan; ^∗P < 0.05 versus WKY + saline group; ^∗∗P < 0.01 versus WKY + saline group; ^#P < 0.05 versus SHR + saline group; ^##P < 0.01 versus SHR + saline group.