ADRB1 gene polymorphism regulated the positive inotropic effect of myocardial insufficiency with metabolic syndrome:a basic experimental research

Abstract

Background The risk of cardiovascular disease (CVD) in metabolic syndrome (MS) patients is significantly higher than that in healthy people, and ADRB1 gene polymorphism is closely associated with CVD. Our previous study found that obesity can lead to the change of β-adrenergic receptor (β-AR) in myocardium, but the mechanism is not clear. The aim of the study was to investigate the effect of ADRB1 gene polymorphism on the β-AR and its downstream signaling molecules involved in a model of myocardial insufficiency with MS. Materials and Methods We constructed the β₁AR-49M (HA-β₁AR-S49G) and β₁AR-389M (HA-β₁AR-R389G) mutant plasmids for cell transfection. cAMP level was assessed by Fluorescence Resonance Energy Transfer (FRET). The Ca²⁺ flow detection was characterized by Fluo-4 indicator calcium concentration assay. H9C2 cardiomyocytes were treated with palmitic acid (PA) to construct the cell injury model. Wistar rats were subjected to normal chow diet (Control group) and high-fat diet (MS group) for 16 weeks. The cardiac function of rats was detected by echocardiography. The positive inotropic effect in vivo was observed by intravenous pumping of Isoproterenol (ISO), and in vitro, muscle force was determined by administering ISO using muscle force measurement system. The protein expression of β-AR and downstream molecular proteins in left ventricular tissue was detected by Western Blot. Results ADRB1 gene polymorphism did not affect the expression of β₁-AR. Moreover, like wild type, carrying β₁AR-389M was most sensitive to Bisoprolol, while β₁AR-49M is most sensitive to Carvedilol. PA intervention resulted in up-regulation of β₁-AR expression with no significant difference between the mutant groups. The inhibitory effect of Bisoprolol in those carrying β₁AR-R389G mutant was stronger than that of carrying β₁AR-S49G mutant. Echocardiographic results indicated that left ventricular systolic and diastolic functions were not impaired in MS group. The positive inotropic effect in MS rats was significantly weaker than that in Control group in vitro, without being impaired in vivo. Conclusions ADRB1 gene polymorphism can lead to the differences on the molecular mechanism and response to β₁AR inhibitors, and especially, carrying the β₁AR-R389G mutant is more conducive to the exertion of the pharmacological effects of Bisoprolol.