ABSTRACT
【Objective】 To investigate the effects of echinacoside （ECH） on mitochondrial biosynthesis and cardiomyocytes’ apoptosis in heart failure （HF） and to explore its related mechanisms. 【Methods】 The experimental animals were divided into three groups： the rat model of HF （HF） was induced by intraperitoneal injection of ISO， and pre-treated with ECH by intraperitoneal injection （ECH） and nomal control （ctrl group）. Cardiac function was detected by echocardiography after 2 weeks of treatment. The ultrastructure of myocardium was observed by transmission electron microscopy and the mitochondrial density and vacuolation rate were analyzed. The expressions of apoptosis-associated proteins were evaluated by Western blotting， and genes related to mitochondrial biosynthesis were examined by Real-time PCR. 【Results】 ECH increased 1eft ventricular ejection fraction （LVEF） and 1eft ventricular fraction shortening （LVFS）， but decreased 1eft ventricular end-systolic diameter （LVEDs） and 1eft ventrieular end-diastolic diameter （LVEDd） when compared to HF group （P<0.01） and improved cardiac function. The myocardial ultrastructure was significantly improved by ECH， the density of regular shapes of mitochondria was increased， and the percentage of vacuolated rate was reduced by ECH （P<0.01）. The expression of anti-apoptotic protein Bcl-2 was upregulated and that of pro-apoptotic protein Bax was downregulated in ECH group. The mRNA of mitochondrial biosynthesis related genes PGC-1， NFR-1， NFR-2 and TFAM was significantly upregulated in ECH group. 【Conclusion】 ECH promotes mitochondrial biosynthesis and inhibits cardiomyocytes’ apoptosis by up-regulating PGC-1/NFR signaling pathway， thus improving cardiac function.
ABSTRACT
In heart failure (HF), the malignant arrhythmias occur frequently; a study demonstrated that upregulation of I KAS resulted in recurrent spontaneous ventricular fibrillation in HF. However, the regulation of SK channels was poorly understood. The activation of SK channels depended on [Ca(2+)]i and PP2A; studies suggested that angiotensin II can regulate them. So, we hypothesized that in HF, the excess of angiotensin may regulate the SK channels and result in the remodeling of SK channels. To test the hypothesis, we used volume-overload-induced HF rat model, treated with captopril, performed whole-cell patch clamp to record apamin-sensitive currents (I KAS), and I-V curve was studied. The sensitivity of I KAS to [Ca(2+)]i was also explored by setting various [Ca(2+)]i (10, 100, 500, 900, 1000, and 10,000 nM), and the steady-state Ca(2+) response of I KAS was attained and performed Hill fitting with the equation (y = 1/[1 + (EC50/x) (n) ]). Immunofluorescent staining, real-time PCR, Western blot were also carried out to furtherly investigate the underlying molecular mechanisms of the regulation. Captopril significantly decreased the mean density of I KAS when [Ca(2+)]i was 500, 900, 1000, and 10000 nM. The Hill fitting showed significantly different EC50 values and the Hill coefficients and showed captopril significantly shifted rightward the steady-state Ca(2+) response of I KAS. The results of real-time PCR and Western blot demonstrated captopril decreased the mRNA and protein expression of SK3 channels. Captopril significantly downregulated the sensitivity of SK channels to [Ca(2+)]i and the SK3 channels expression in HF, and reversed the SK channels remodeling.
