| Aims:Cirsimaritin, a natural flavone, has been reported to exert sufficient activities including anti-tumor, antioxidant, antibacterial, anti-inflammation, renal protection and so on. However, despite these pharmacological studies, whether cirsimaritin alleviates heart failure is still unknown.Main methods:We examined the effect and mechanism of cirsimaritin on rat model with heart failure as well as in neonatal cardiomyocytes. This rat model was induced by subcutaneous injection of norepinephrine(ISO). These animals were weighed and randomly divided into 2 groups: normal group(n=10), model group(ISO group)(n=80). Rats in the model group were injected with 170mg/kg norepinephrine every24 hours for two times. The qualified rats(LVEF<45%) in ISO group were randomly separated into 5 groups: control group(n = 15), enalapril group(enalapril 1 mg / kg /day group, n = 12), cirsimaritin low dose group(cirsimaritin 25 mg / kg / day group,n = 11), cirsimaritin medium dose group(cirsimaritin 50 mg / kg / day group, n = 10),cirsimaritin high dose group(cirsimaritin 100 mg / kg / day group, n = 12). Drugs were administered orally for 8 weeks. Hemodynamic indexes including left ventricular systolic pressure(LVSP), left ventricular end diastolic pressure(LVEDP),the maximum rising and decreasing rate of left ventricular pressure(+ dp / dtmax and –dp / dtmax) were measured with biological function experimental system measurement,and the information was analyzed with BL-New Century biological signal display and processing software. At the last day, rats were scarified through carotid artery bloodletting, and the blood was frozen and detected for neuroendocrine indicators.Hearts were removed, washed with precooled saline and blotted with filter papers.Then the left ventricle and interventricular septum separated from the right ventricular free wall was weighed and get the left ventricular mass(LVM) and the left ventricular mass index(LVMI). Part of the left ventricular tissue was stored in liquid nitrogen to detect other indicators. Pathological sections of hearts were made, stained with H&E and Masson and observed with optical microscope for the following lesions: edema, inflammatory cell infiltration and connective tissue hyperplasia on the myocardial interstitial; hypertrophy, degeneration and necrosis of myocardial cell.These lesions were scored from 1 to 5 points based on the severity of lesions, and 0meant no lesions. All scores of animals in each group were accumulated, and the average value was taken. The hydroxyproline in ventricular muscle sample was measured by alkali hydrolysis method and the concentration of each cytokine was measured by ELISA kits. Expression and activity of MMP-2&9 was assayed by real-time PCR and gelatin zymography assay, respectively. Protein levels were determined by Western blot.Key findings:Administration of isoproterenol led to a serious heart failure, as evidenced by the up-regulation of heart rate, mass index and end diastolic pressure of left ventricular,while by the down-regulation of left ventricular systolic pressure, maximal rate of pressure rise or decline of left ventricular. Pretreatment of cirsimaritin significantly ameliorated these cardiac parameters in a dose-dependent manner. In addition,cirsimaritin remarkably inhibited serum levels of Ang II, NE, TNF-α and BNP in rats with heart failure and attenuated the cardiac histological changes. Moreover, matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were also suppressed by cirsimaritin. Furthermore, myocardial autophagy was significantly promoted by cirsimaritin in vivo and in vitro through inhibiting AKT1-RPS6KB1 signaling.Significance:Cirsimaritin mitigates cardiac remodeling and left ventricular dysfunction through augmenting myocardial autophagy and decreasing matrix metalloproteinase-2&9 activities, suggesting its potential purpose in patients with congestive heart failure. |
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