랫드 심근 허혈/재관류 손상 동물모델에서 좌심실 이완기능 장애 완화에 대한 메트포르민 또는 사파논A의 심장보호 효과

Abstract

The increased incidence of myocardial infarction (MI) has emerged globally as a leading cause of cardiovascular morbidity and mortality. In the development of new drugs, the evaluation of cardiac function is important factor in the withdrawal of drug candidates. In addition, as life expectancy increases, the prevalence of metabolic syndrome is gradually increasing, and metabolic syndromes such as diabetes, abdominal obesity, dyslipidemia, and hypertension are the main causes of cardiovascular disease. The aim of this study was to establish a rat myocardial ischemia and reperfusion (I/R) injury model similar to human acute MI and investigate cardiac function commonly referred to as left ventricular (LV) function including LV systolic and diastolic function using echocardiographic evaluation. Male Sprague-Dawley rats, 8-9-week-old, were ligated and reperfused the left anterior descending coronary artery (LAD) for 30 minutes under ventilation. Echocardiography was performed under anesthesia after the induction of MI according to the experimental plan. Among the echocardiographic indices, EF and FS represent the left ventricular systolic function in tree-dimensional and two-dimensional meanings respectively. To assess the left ventricular diastolic function, the values of peak velocity of the transmitral flow at early filling (E), the early diastolic mitral annular velocity (E’) at the medial mitral annulus, and E/E’ ratio were measured. In the preliminary study, the EF and FS values of rats with MI were significantly decreased compared with those of the sham group at 2 hours and on day 1 (P<0.01). However, the significantly decreased E’ and increased E/E’ values of MI group were shown compared with those of sham group during the entire experimental period. These results indicate that, unlike left ventricular systolic function, left ventricular diastolic function does not recover at the early phase of rat myocardial I/R injury model. Moreover, this acute myocardial infarction animal model and echocardiographic assessment of cardiac function show the importance of the left ventricular diastolic function, which is currently highlighted in patients with heart failure in human. In this study, in a rat myocardial I/R injury model, we can evaluate the efficacy study of candidates for new drug development especially using echocardiographic evaluation of left ventricular diastolic function, and applied metformin and sappanone A. Metformin, dimethyl biguanide as a first-line treatment for type Ⅱ diabetes, significantly improved left ventricular systolic function including EF and FS values on days 3 and 7 after MI surgery. In addition, metformin resulted in recovery of left ventricular diastolic function in the early phase of rat ischemic reperfusion injury in this model. It was also possible to confirm the cardioprotective effect of metformin in histopathological results, in line with echocardiographic results. Sappanone A, isolated from heartwood Caesalpinia sappan, homoisoflavanone, has proven anti-inflammatory effects with cells and LPS-induced bone loss mouse model. Sapannone A administration significantly attenuated left ventricular systolic and diastolic dysfunction in a rat myocardial I/R injury model in the early phase of MI. Also, myocardial infarct size, serum cardiac marker assay, histopathological assessment of inflammatory cells infiltration of rat hearts, transcriptome analysis of rat left ventricles showed that 50 mg/kg sappanone A has a cardioprotective effect. Therefore, this rat myocardial I/R injury model using multimodal assessment of cardiac function including echocardiographic evaluation of left ventricular systolic and diastolic function, serum cardiac marker, myocardial infarct size, histopathologic evaluation, and mRNA sequencing can be widely used in translational research and in the development of new heart failure-related drugs.