Fluvastatin attenuated ischemia/reperfusion-induced autophagy and apoptosis in cardiomyocytes through down-regulation HMGB1/TLR4 signaling pathway.

Abstract

Fluvastatin, a traditional fat-decreasing drug, is widely used for curing cardiovascular disease. Previous reports demonstrated that fluvastatin pretreatment protected against myocardial ischemia/reperfusion (I/R) by inhibiting TLR4 signaling pathway and/or reducing proinflammatory cytokines. However, whether fluvastatin has a cardioprotective effect against apoptosis and autophagy remains unknown. This study aims to evaluate whether the cardioprotective role of fluvastatin in I/R is mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) pathway via anti-apoptotic and anti-autophagic functions. Sprague-Dawley rats were anesthetized, artificially ventilated and subjected to 30 min of coronary occlusion, followed by 4 h of reperfusion. The animals were randomized into four groups: (i) Sham operation; (ii) I/R; (iii) I/R + low-dosage fluvastatin (10 mg/kg); and (iv) I/R + high-dosage fluvastatin (20 mg/kg). After reperfusion, the hemodynamic parameters, myocardial infarct size, structural alteration of myocardium, apoptosis index, pro-inflammatory cytokine production, Beclin-1, Light chain 3 (LC3), HMGB1, TLR4 and Nuclear factor kappa B (NF-κB) protein levels were measured and recorded. It was found that fluvastatin preconditioning improved left ventricular dysfunction, reduced HMGB1/TLR4/NF-κB expressions, and inhibited cardiomyocyte apoptosis, autophagy, and inflammation reaction. Moreover, treatment with fluvastatin ameliorated myocardial injury by reducing infarct size, causing less damage to cardiac structure, downregulating autophagy-related protein expression and releasing pro-inflammation mediators. Our findings indicate that fluvastatin exerts beneficial effects on cardiac ischemic damage, which may be associated with its anti-autophagic and anti-apoptotic functions via inhibition of HMGB1/TLR4-related pathway during I/R injury.

• Authors: Hua-Sheng Ding, Jun Yang, Jian Yang, Xin Guo, Yan-Hong Tang, Yan Huang, Zhen Chen, Zhi-Xing Fan, Cong-Xin Huang
• Journal: Molecular biology reports (Mol Biol Rep) Vol. 48 Issue 5 Pg. 3893-3901 (May 2021) ISSN: 1573-4978 [Electronic] Netherlands
• PMID: 34032975 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• HMGB1 Protein
• Hbp1 protein, rat
• NF-kappa B
• Tlr4 protein, rat
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Fluvastatin

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Autophagy (drug effects, physiology)
• Cardiotonic Agents (metabolism, pharmacology)
• China
• Fluvastatin (metabolism, pharmacology)
• HMGB1 Protein (genetics, metabolism)
• Male
• Myocardial Infarction (metabolism)
• Myocardial Ischemia (metabolism)
• Myocardial Reperfusion Injury (metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• NF-kappa B (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, prevention & control)
• Signal Transduction
• Toll-Like Receptor 4 (genetics, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)