Atorvastatin Improves Doxorubicin-Induced Cardiac Dysfunction by Modulating Hsp70, Akt, and MAPK Signaling Pathways

Abstract

Atorvastatin is a lipid-regulating drug that is commonly used in clinical practice and can stabilize plaques. Increasing evidence shows that statins have anti–heart failure (HF) effects, but their specific mechanism is not clear. The purpose of this study was to investigate the cardioprotective effects of atorvastatin on HF in rats and its mechanism. Continuous intraperitoneal injection of 2.5 mg/kg/w doxorubicin for 6 weeks, with a cumulative dose of 15 mg/kg, was used to induce a rat model of HF. Then, the rats were treated with low-dose atorvastatin, high-dose atorvastatin, or saline for 4 weeks. In the DOX-treated groups, echocardiography showed decreases in left ventricular ejection fraction and fractional shortening and increases in left ventricular end-diastolic diameter and left ventricular posterior wall thickness compared with those in the control group, and increased levels of brain natriuretic peptide and Hsp70 were also found in the doxorubicin-treated groups. Compared with saline intervention, atorvastatin ameliorated left ventricular ejection fraction, fractional shortening, left ventricular end-diastolic diameter, and left ventricular posterior wall thickness (a significant difference was observed only in the high-dose group) and reduced serum brain natriuretic peptide. Hematoxylin and eosin staining showed that atorvastatin ameliorated myocardial injury. The improvement in cardiac function induced by atorvastatin was accompanied by increased Hsp70 expression, decreased p-ERK and p-JNK expression, and a reduction in myocardial fibrosis shown by Masson staining. In addition, atorvastatin had a protective effect on the myocardial apoptosis signaling pathway, with increased p-Akt expression and downregulated cleaved caspase-3 expression, and the reduction in myocardial apoptosis was confirmed by a TUNEL assay. Therefore, our experiments demonstrated that atorvastatin may protect cardiac function by modulating Hsp70, p-Akt, p-ERK, and p-JNK signaling to reduce myocardial fibrosis and myocardial apoptosis.

Atorvastatin attenuates TGF‑β1‑induced fibrogenesis by inhibiting Smad3 and MAPK signaling in human ventricular fibroblasts

“…However, pre-incubation with ATV inhibited the TGF-β1-stimulated fibrotic response in hVFs. The results were in agreement with earlier studies, which reported that ATV prevents advanced glycation end products-, angiotensin II-, hypertension-, aldosterone-and doxorubicin-induced cardiac fibrosis (16)(17)(18)(19)(20).…”

“…Furthermore, statins have also been reported to possess pleiotropic cardiovascular effects, including reduced oxidative stress and inflammation, decreased platelet adhesion, improved endothelial function and enhanced atherosclerotic plaque stability (13)(14)(15). In addition, previous studies have shown that atorvastatin (ATV), a member of the statin family, exerts potential anti-myocardial fibrotic properties (16)(17)(18)(19)(20). Nevertheless, to the best of our knowledge, the molecular mechanism involved in the effect of ATV on cardiac fibrosis remains to be clarified, and limited information is available concerning the possible impact of ATV on TGF-β1-induced human ventricular fibroblast (hVF) proliferation and myofibroblast differentiation.…”

Early Moderate Intensity Aerobic Exercise Intervention Prevents Doxorubicin-caused Cardiac Dysfunction through Inhibition of Cardiac Fibrosis and Inflammation

“…It has been revealed that mitochondrial reactive oxygen species-induced ERK1/2 activation was required for DOX-induced apoptosis and cardiotoxicity [39]. Although there was no direct evidence suggested that the ERK pathway was involved in the DOX-stimulated fibrosis, a couple of studies have shown that treatments that improved cardiac function and reduced myocardial fibrosis were accompanied by decreased phospho-ERK [40,41], which were consistent with our findings. Furthermore, we demonstrated that the increased expression of Sp1 by DOX was ameliorated through exercise intervention.…”

Ethanol exposure in prenatal and early postnatal induced cardiac injury in rats: involvement of oxidative stress, Hsp70, ERK 1/2, JNK, and apoptosis in a 3-month follow-up study

“…All data are expressed as the mean ± SD (n = 8). ***p < 0.001 vs C-PN21; ### p < 0.001 vs C-PN90 apoptosis (Gao et al 2018). JNK activation has commonly been associated with cell inflammation and apoptosis, whereas the ERK pathway is implicated in cellular survival and growth (Sun et al 2015b).…”