Carvedilol alleviates diabetic cardiomyopathy in diabetic rats

Abstract

Diabetic cardiomyopathy (DCM) is characterized by structural and functional changes in the myocardium. Several studies have revealed that myocardial apoptosis and fibrosis occur during DCM. Studies have also indicated that oxidative stress may be a major factor associated with the development of DCM. Protein kinase C (PKC)β 2 has been demonstrated to be activated in diabetic rats, and overexpression of PKCβ 2 in the myocardium may result in cardiac hypertrophy and fibrosis. The P66 shc adaptor protein, which is mediated by PKCβ, serves an important role in apoptosis during oxidative stress. The aim of the present study was to investigate whether the PKCβ 2 /P66 shc oxidative stress pathway is associated with DCM, and to investigate the role and mechanisms of carvedilol in preserving cardiac function. Experimental diabetic rat models were induced by streptozotocin treatment accompanied by high energy intake. Carvedilol was orally administrated at a dose of 1 or 10 mg/kg/day. Cardiac function was evaluated by serum N-terminal pro-B-type natriuretic peptide level and cardiac ultrasound. Myocardial inflammation, oxidative stress, apoptosis and fibrosis were assessed by histopathological and echocardiographic analyses and tests for oxidative markers. Associated proteins and factors were examined by immunohistochemical and western blot analyses. Rats in the diabetes mellitus group exhibited significantly decreased systolic cardiac function along with elevated expression levels of phosphorylated (p)-PKCβ 2 , phos-P66 shc , caspase-3, malondialdehyde, collagen type I, tumor necrosis factor-α and interleukin-1β, which were accompanied by disorder in metabolic processes. Treatment with carvedilol reversed these changes. Thus, the present results suggest that the PKCβ 2 /P66 shc signaling pathway may be associated with diabetic cardiomyopathy; furthermore, carvedilol, as a novel β-receptor blocker, may protect the myocardium from injury by suppressing the myocardial inflammatory response, fibrosis, P66 shc-mediated oxidative stress and subsequent apoptosis in myocardial tissue. Consequently, carvedilol may have potential as a therapy for the treatment of DCM.

Metabolic effects of carvedilol through β‐arrestin proteins: investigations in a streptozotocin‐induced diabetes rat model and in C2C12 myoblasts

“…The authors concluded that they were associated and involved in the pathogenesis of diabetic cardiomyopathy. The effect of carvedilol in control animals was not investigated in this study and the authors have not linked their findings with GPCR coupling or biased agonist activity of carvedilol (Zheng et al, 2017(Zheng et al, , 2019.…”

Research update for articles published in EJCI in 2017

“…The translational value of this paper was that carvedilol may be beneficial in patients with uncontrolled diabetes, decreasing the progression of diabetic cardiomyopathy or hyperglycaemia-related oxidative stress in skeletal muscle. Zheng et al later confirmed these findings in the same rat model, 5 and demonstrated that oral carvedilol suppressed myocardial inflammatory response, fibrosis, P66 shc -mediated oxidative stress and apoptosis in cardiac muscle. Also, in a high-fat diet model of type 2 diabetes mellitus and obesity, Wang et al 6 showed that β2-adrenergic receptor inhibition by carvedilol resulted in decreased contractile dysfunction, although the authors could not demonstrate the relationship with decreased oxidative stress.…”

Carvedilol activates nuclear factor E2-related factor 2/ antioxidant response element pathway to inhibit oxidative stress and apoptosis of retinal pigment epithelial cells induced by high glucose

“…In addition, CAR is also available for the treatment of diabetic complications. For instance, CAR protects myocardium from injury by inhibiting myocardial inflammatory response, fibrosis, P66shc-mediated oxidative stress and myocardial apoptosis, suggesting that CAR may have potential for the treatment of diabetic cardiomyopathy [ 28 ]. Another example of this was the study carried out by Morsy who suggested that CAR protected rats from early diabetic nephropathy induced by streptozotocin, partially due to its antioxidant, anti-inflammatory activities and ability to alleviate podocyte damage [ 29 ].…”