Cardiomyocyte β2‐Adrenergic Receptor Plays A Protective Role in Cardiac Fibrosis

Abstract

BackgroundChronic stimulation of β adrenergic receptor (βAR) has been implicated in cardiac remodeling including hypertrophy and fibrosis associated with heart failure. Previous studies indicate a role of β2AR on inhibiting collagen production in cultured cardiac fibroblasts, however, our recent studies show that global deletion of β2AR prevent cardiac fibrosis in diabetic cardiomyopathy. Therefore, this study aims to determine the specific role of cardiomyocyte β2AR in cardiac function and the development of cardiac fibrosis in vivo.Methods2‐month old male β2AR flox/flox (f/f) mice (n=10) and cardiomyocyte‐specific knockout of β2AR (CKO) mice (n=10) were fed with either normal chow (NC), or high fat diet (HFD) for 6 months to induce obesity and diabetes. Echocardiography was performed using a Vevo 2100 imaging system from VisualSonics. Biochemistry and histological analyses were performed on heart tissues. Real‐time PCR was performed for mRNA expression examination.ResultsWhile cardiac function was normal at 2‐month old CKO mice, a significant decrease in cardiac contractility was observed in CKO mice compared to f/f mice at 8‐month old age (EF%: CKO 48.43 ± 1.314 vs. f/f 52.69 ± 0.8270, p<0.05). Moreover, HFD feeding exacerbated cardiac dysfunction in CKO mice when compared to f/f mice (EF%: CKO 42.93 ± 0.69 vs. f/f 46.79 ± 0.76, p<0.001). CKO mice also exhibited diastolic dysfunction (IVRT: CKO 20.23 ± 0.30 vs. f/f 16.83 ± 0.23, p<0.0001), which was exacerbated after HFD feeding (IVRT, CKO 24.75 ± 0.50 vs. f/f 19.94 ± 0.45, p<0.0001). The observed cardiac dysfunction was associated with severe cardiac fibrosis in 8‐month old CKO mice, and HFD feeding leads to further exacerbation in cardiac fibrosis. Cardiac fibrosis was validated with elevated protein expression of connective tissue growth factor (CTGF), and significant upregulations of mRNA expression of CTGF, α smooth muscle actin (α‐SMA), and collagen 1 in CKO HFD mice.ConclusionsThis study elucidates that cardiomyocyte β2AR is essential to maintain normal cardiac function and plays a protective role against the development of cardiac fibrosis in aging and HFD feeding in vivo.Support or Funding InformationNIH HL113413, HL147264, VABX002900