科研之友
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摘要
OBJECTIVE To investigate the mechanism by which athycaltide-1, a novel peptide, acts on calmodulin-dependent protein kinase Ⅱ(CaMK Ⅱ) and ameliorates cardiac hypertrophy. METHODS Male SD rats(180-220 g) were divided into three groups: control group, myocardial hypertrophy group(ISO) and athycaltide-1 treatment group(Athycaltide-1). The model of cardiac hypertrophy was prepared by subcutaneous injection of isoproterenol(ISO). The athycaltide-1 group was given intraperitoneal injection of 15 mg·kg-1 body weight peptide as giving isoproterenol. Heart weight(HW), left ventricular mass(LVW) and lung weight(LUW) were normalized to body weight(BW) to assess pathological changes in cardiac structure. Cross-sectional area and myocardial fibrosis were measured by HE and Masson staining.Western blotting was used to detect LC3B, p-Akt/Akt,p-mTOR/mTOR for autophagy pathway protein expression, respectively. Co-immunoprecipitation(CO-IP) were performed to detect binding of CaMKⅡ to ubiquitin molecules. RESULTS Autophagy analysis showed that in the ISO treated tissue, the LC3Ⅱ/LC3Ⅰ ratio decreased(P<0.05), while athycaltide-1 administration reversed the decrease(P<0.05). Athycaltide-1 reduced the expression of p-Akt and p-m TOR proteins(P<0.05) that are activated by ISO treatment(P<0.05). According to the trend of CO-IP results, compared with the trend of ubiquitin in the input,the ubiquitination of CaMK Ⅱ was clearly opposite, indicating that CaMK Ⅱ could be degredated by ubiquitin.CONCLUSION These findings reveal the mechanism of athycaltide-1 attenuating cardiac hypertrophy. Athycaltide-1 could activate autophagy via inhibiting PI3K/Akt/m TOR signaling pathways, and meanwhile athycaltide-1 also promotes the ubiquitination and degradation of CaMKⅡ.Thus, it is implied that the athycaltide-1 may target CaMKⅡ to induce its degradation, thereby reversing the excessive activation of the PI3K/Akt/m TOR pathway, ameliorating myocardial hypertrophy caused by ISO.
