Abstract
Cardiac hypertrophy can lead to congestive heart failure and is a leading cause of morbidity and mortality worldwide. In recent years, it has been essential to find the treatment and prevention of cardiac hypertrophy. Betulinic acid (BA), the main active ingredient in many natural products, is known to have various physiological effects. However, as the potential effect of BA on cardiac hypertrophy and consequent renal dysfunction is unknown, we investigated the effect of BA on isoprenaline (ISO)-induced cardiac hypertrophy and related signaling. ISO was known to induce left ventricular hypertrophy by stimulating the β2-adrenergic receptor (β2AR). ISO was injected into Sprague Dawley rats (SD rats) by intraperitoneal injection once a day for 28 days to induce cardiac hypertrophy. From the 14th day onwards, the BA (10 or 30 mg/kg/day) and propranolol (10 mg/kg/day) were administered orally. The study was conducted in a total of 5 groups, as follows: C, control; Is, ISO (10 mg/kg/day); Pr, positive-control, ISO + propranolol (10 mg/kg/day); Bl, ISO + BA (10 mg/kg/day); Bh, ISO + BA (30 mg/kg/day). As a result, the total cardiac tissue and left ventricular tissue weights of the ISO group increased compared to the control group and were significantly reduced by BA treatment. In addition, as a result of echocardiography, the effect of BA on improving cardiac function, deteriorated by ISO, was confirmed. Cardiac hypertrophy biomarkers such as β-MHC, ANP, BNP, LDH, and CK-MB, which were increased by ISO, were significantly decreased by BA treatment. Also, the cardiac function improvement effect of BA was confirmed to improve cardiac function by inhibiting calcineurin/NFATc3 signaling. Renal dysfunction is a typical complication caused by cardiac hypertrophy. Therefore, the study of renal function indicators, creatinine clearance (Ccr) and osmolality (BUN) was aggravated by ISO treatment but was significantly restored by BA treatment. Therefore, it is thought that BA in cardiac hypertrophy can be used as valuable data to develop as a functional material effective in improving cardiac-renal dysfunction.
Highlights
Heart failure is a risk factor of many cardiovascular diseases and is considered globally as one of the causes of morbidity and mortality [1]
Cardiac hypertrophy is a crucial reason for heart failure; the preparation of therapeutic solutions and prevention of cardiac hypertrophy is important
Chronic β-adrenergic receptors are located in cardiomyocytes, fibroblasts and endothelial cells. βAR stimulation induces an increase in the size of cardiomyocytes
Summary
Heart failure is a risk factor of many cardiovascular diseases and is considered globally as one of the causes of morbidity and mortality [1]. Cardiac hypertrophy is a leading cause of heart failure and is induced by pathological stimuli such as myocardial infarction, cardiac fibrosis, inflammation, and ventricular remodeling [2]. Cardiac hypertrophy is induced by biomechanical stress and characterized by thickening of the ventricle wall in the heart, the growth of heart mass and cardiomyocytes [3]. Chronic cardiac hypertrophy caused apoptosis of cardiomyocytes and would cause heart failure and sudden death. Β-adrenergic signaling, which was activated by sympathetic stimuli, plays an important role in progression of cardiac hypertrophy [4]. Chronic β-adrenergic receptors (βAR) are located in cardiomyocytes, fibroblasts and endothelial cells. ΒAR stimulation induces an increase in the size of cardiomyocytes. Calcineurin-NFAT signaling is important in regulating cardiac hypertrophy [6]. Propranolol lowered heart weight and the thickness of the left ventricular wall in mice and is effective in cardiac function [7,8]
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