Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway

Abstract

Background/Aims: Many clinical and experimental studies have shown that treatment with statins could prevent myocardial hypertrophy and remodeling induced by hypertension and myocardial infarction. But the molecular mechanism was not clear. We aimed to investigate the beneficial effects of atorvastatin on hypertension-induced myocardial hypertrophy and remodeling in spontaneously hypertensive rats (SHR) with the hope of revealing other potential mechanisms or target pathways to interpret the pleiotropic effects of atorvastatin on myocardial hypertrophy. Methods: The male and age-matched animals were randomly divided into three groups: control group (8 WKY), SHR (8 rats) and intervention group (8 SHR). The SHR in intervention group were administered by oral gavage with atorvastatin (suspension in distilled water, 10 mg/Kg once a day) for 6 weeks, and the other two groups were administered by gavage with equal quantity distilled water. Blood pressure of rats was measured every weeks using a standard tail cuff sphygmomanometer. Left ventricular (LV) dimensions were measured from short-axis views of LV under M-mode tracings using Doppler echocardiograph. Cardiomyocyte apoptosis was assessed by the TUNEL assay. The protein expression of C/EBPβ, PGC-1α and UCP3 were detected by immunohistochemistry or Western blot analysis. Results: At the age of 16 weeks, the mean arterial pressure of rats in three groups were 103.6±6.1, 151.8±12.5 and 159.1±6.2 mmHg respectively, and there wasn’t statistically significant difference between the SHR and intervention groups. Staining with Masson’s trichrome demonstrated that the increased interstitial fibrosis of LV and ventricular remodeling in the SHR group were attenuated by atorvastatin treatment. Echocardiography examination exhibited that SHR with atorvastatin treatment showed an LV wall thickness that was obviously lower than that of water-treated SHR. In hypertrophic myocardium, accompanied by increasing C/EBPβ expression and the percentage of TUNEL-positive cells, the expression of Bcl-2/Bax ratio, PGC-1α and UCP3 were reduced, all of which could be abrogated by treatment with atorvastatin for 6 weeks. Conclusion: This study further confirmed that atorvastatin could attenuate myocardial hypertrophy and remodeling in SHR by inhibiting apoptosis and reversing changes in mitochondrial metabolism. The C/EBPβ/PGC-1α/UCP3 signaling pathway might also be important for elucidating the beneficial pleiotropic effects of atorvastatin on myocardial hypertrophy.

Diverging targets mediate the pathological role of miR-199a-5p and miR-199a-3p by promoting cardiac hypertrophy and fibrosis

“…These results were supported by previous reports that PGC-1α activation alleviated cardiac fibrosis and remodeling. 32 , 33 , 34 We also demonstrated that Rb-1 mediated miR-199a-3p in promoting cardiomyocyte hypertrophy with an increase of nuclear translocation of transcription factor E2F2 in NMVCs. Adult mammalian cardiomyocytes may reenter the cell cycle and cause cardiac hypertrophy, 35 , 36 and activation of the Rb/E2f signal was reported to participate in cell-cycle progression of cardiomyocytes 37 , 38 and cardiomyocyte hypertrophy.…”

Caduet enhances connexin 43 phosphorylation in left ventricular and thoracic aorta of SH model rats

“…Furthermore, ventricular remodeling is a risk factor of various severe arrhythmias, as well as sudden mortality (24). Owing to improved compliance, AM + AT have been used for treating hypertension and hyperlipidemia, and can protect vascular smooth muscle and myocardium from remodeling (25,26). Caduet is a single pill containing AM and AT, which blocks Ca 2+ transmembrane influx, inhibits β-Hydroxy β-methylglutaryl-coenzyme A reductase, decreases vascular resistance and reverses ventricular remodeling (27).…”

Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy

“…Since PGC-1α was also upregulated by THC, the interactions between PGC-1α and UPR mt were further investigated. PGC-1α mediates the anticardiac hypertrophic role of several medicines [37,38]. It also exerts a cardioprotective role in ischemia and reperfusion-induced and exhaustive exerciseinduced heart injury due to its antioxidant activity [39,40].…”