Artesunate attenuates isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation.

Cardiac Hypertrophy is an adaptive response of the body to physiological and pathological stimuli, which increases cardiomyocyte size, thickening of cardiac muscles and progresses to heart failure. Downregulation of SIRT1 in cardiomyocytes has been linked with the pathogenesis of cardiac hypertrophy. The present study aimed to investigate the effect of Artesunate against isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation. Experimental cardiac hypertrophy was induced in rats by subcutaneous administration of isoprenaline (5 mg/kg) for 14 days. Artesunate was administered simultaneously for 14 days at a dose of 25 mg/kg and 50 mg/kg. Artesunate administration showed significant dose dependent attenuation in mean arterial pressure, electrocardiogram, hypertrophy index and left ventricular wall thickness compared to the disease control group. It also alleviated cardiac injury biomarkers and oxidative stress. Histological observation showed amelioration of tissue injury in the artesunate treated groups compared to the disease control group. Further, artesunate treatment increased SIRT1 expression and decreased NF-kB expression in the heart. The results of the study show the cardioprotective effect of artesunate via SIRT1 inhibiting NF-κB activation in cardiomyocytes.

Emerging therapeutic avenues in cardiac amyloidosis.

Cardiac Amyloidosis (CA) is a toxic infiltrative cardiomyopathy occurred by the deposition of the amyloid fibres in the extracellular matrix of the myocardium. This results in severe clinical complications such as increased left ventricular wall thickness and interventricular stiffness, a decrease in left ventricular stroke volume and cardiac output, diastolic dysfunction, arrhythmia, etc. In a prolonged period, this condition progresses into heart failure. The amyloid fibres affecting the heart include immunoglobulin light chain (AL - amyloidosis) and transthyretin protein (ATTR - amyloidosis) misfolded amyloid fibres. ATTRwt has the highest prevalence of 155 to 191 cases per million while ATTRv has an estimated prevalence of 5.2 cases per million. The pathological findings and therapeutic approaches developed recently have aided in the treatment regimen of cardiac amyloidosis patients. In recent years, understanding the pathophysiology of amyloid fibres formation and mechanistic pathways triggered in both types of cardiac amyloidosis has led to the development of new therapeutic approaches and agents. This review focuses on the current status of emerging therapeutic agents in clinical trials. Earlier, melphalan and bortezomib in combination with alkylating agents and immunomodulatory drugs were used as a standard therapy for AL amyloidosis. Tafamidis, approved recently by FDA is used as a standard for ATTR amyloidosis. However, the emerging therapeutic agents under development for the treatment of AL and ATTR cardiac amyloidosis have shown a potent and rapid effect with a safety profile.

mAKAPß signalosome: A potential target for cardiac hypertrophy.

Pathological cardiac hypertrophy is the result of a prolonged increase in the workload of the heart that activates various signaling pathways such as MAPK pathway, PKA-dependent cAMP signaling, and CaN-NFAT signaling pathway which further activates genes for cardiac remodeling. Various signalosomes are present in the heart that regulates the signaling of physiological and pathological cardiac hypertrophy. mAKAPß is one such scaffold protein that regulates signaling pathways involved in promoting cardiac hypertrophy. It is present in the outer nuclear envelope of the cardiomyocytes, which provides specificity of the target toward the heart. In addition, nuclear translocation of signaling components and transcription factors such as MEF2D, NFATc, and HIF-1α is facilitated due to the localization of mAKAPß near the nuclear envelope. These factors are required for activation of genes promoting cardiac remodeling. Downregulation of mAKAPß improves cardiac function and attenuates cardiac hypertrophy which in turn prevents the development of heart failure. Unlike earlier therapies for heart failure, knockout or silencing of mAKAPß is not associated with side effects because of its high specificity in the striated myocytes. Downregulating expression of mAKAPß is a favorable therapeutic approach toward attenuating cardiac hypertrophy and hence preventing heart failure. This review discusses mAKAPß signalosome as a potential target for cardiac hypertrophy intervention.