Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene.

Abstract

BACKGROUND:

Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial.

METHODS AND RESULTS:

Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene.

CONCLUSION:

Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

• Authors: Shengqi Huo, Wei Shi, Haiyan Ma, Dan Yan, Pengcheng Luo, Junyi Guo, Chenglong Li, Jiayuh Lin, Cuntai Zhang, Sheng Li, Jiagao Lv, Li Lin
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2021 Pg. 6699054 ( 2021) ISSN: 1942-0994 [Electronic] United States
• PMID: 33824698 (Publication Type: Journal Article, Retracted Publication)
• Copyright: Copyright © 2021 Shengqi Huo et al.

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Interleukin-6
• Phb2 protein, mouse
• Prohibitins
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Tumor Necrosis Factor-alpha
• Raloxifene Hydrochloride

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antioxidants (pharmacology, therapeutic use)
• Cardiomegaly (metabolism, prevention & control)
• Cell Line
• Heart Failure (metabolism, prevention & control)
• Interleukin-6 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mitophagy
• Myocytes, Cardiac (drug effects, metabolism)
• Oxidative Stress
• Prohibitins
• Raloxifene Hydrochloride (pharmacology, therapeutic use)
• STAT3 Transcription Factor (metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)