Abstract
The forkhead/winged helix transcription factor (Fox) p3 can regulate the expression of various genes, and it has been reported that the transfer of Foxp3-positive T cells could ameliorate cardiac hypertrophy and fibrosis. Triptolide (TP) can elevate the expression of Foxp3, but its effects on cardiac hypertrophy remain unclear. In the present study, neonatal rat ventricular myocytes (NRVM) were isolated and stimulated with angiotensin II (1 μmol/L) to induce hypertrophic response. The expression of Foxp3 in NRVM was observed by using immunofluorescence assay. Fifty mice were randomly divided into five groups and received vehicle (control), isoproterenol (Iso, 5 mg/kg, s.c.), one of three doses of TP (10, 30, or 90 μg/kg, i.p.) for 14 days, respectively. The pathological morphology changes were observed after Hematoxylin and eosin, lectin and Masson’s trichrome staining. The levels of serum brain natriuretic peptide (BNP) and troponin I were determined by enzyme-linked immunosorbent assay and chemiluminescence, respectively. The mRNA and protein expressions of α- myosin heavy chain (MHC), β-MHC and Foxp3 were determined using real-time PCR and immunohistochemistry, respectively. It was shown that TP (1, 3, 10 μg/L) treatment significantly decreased cell size, mRNA and protein expression of β-MHC, and upregulated Foxp3 expression in NRVM. TP also decreased heart weight index, left ventricular weight index and, improved myocardial injury and fibrosis; and decreased the cross-scetional area of the myocardium, serum cardiac troponin and BNP. Additionally, TP markedly reduced the mRNA and protein expression of myocardial β-MHC and elevated the mRNA and protein expression of α-MHC and Foxp3 in a dose-dependent manner. In conclusion, TP can effectively ameliorate myocardial damage and inhibit cardiac hypertrophy, which is at least partly related to the elevation of Foxp3 expression in cardiomyocytes.
Highlights
Cardiac hypertrophy is a pathological feature of various cardiac diseases, including hypertension, cardiomyopathy, valvular dysfunction, myocardial infarction, etc., and the strongest predictor for the development of heart failure, arrhythmia, and sudden death (van Berlo et al, 2013; Frieler and Mortensen, 2015)
Foxp3 can depress the activation of immune cells and their migration to myocardium (Matsumoto et al, 2011), reduce the cardiac interstitial inflammatory cell infiltration and the secretion of cytokines, and ameliorate cardiac hypertrophy and myocardial damage induced by angiotensin II (AngII) or high blood pressure
After stimulation with AngII for 24 h, the surface area of primary cardiomyocytes significantly increased by 1.83-folds compared to the control (AngII vs. control: 3849 ± 81 vs. 1379 ± 31 μm2; p < 0.01)
Summary
Cardiac hypertrophy is a pathological feature of various cardiac diseases, including hypertension, cardiomyopathy, valvular dysfunction, myocardial infarction, etc., and the strongest predictor for the development of heart failure, arrhythmia, and sudden death (van Berlo et al, 2013; Frieler and Mortensen, 2015). It has been identified as a significant independent risk factor for cardiac diseases and suggested to be the primary therapeutic goal for hypertension and chronic heart failure (Chemaly et al, 2013; Verschuren et al, 2014; Ikeda et al, 2015). It has been reported that adoptive transfer of Treg cells into AngII–infused hypertensive mice could improve cardiac hypertrophy and ameliorate cardiac fibrosis despite sustained hypertension (Kvakan et al, 2009; Kasal et al, 2012)
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