Isoproterenol-Induced Cardiomyopathy Recovery Intervention: Amlexanox and Forskolin Enhances the Resolution of Catecholamine Stress-Induced Maladaptive Myocardial Remodeling

Gabriel Komla Adzika; Hongjian Hou; Adebayo Oluwafemi Adekunle; Ruqayya Rizvi; Joseph Adu-Amankwaah; Wenkang Shang; Kexue Li; Qi-Ming Deng; Richard Mprah; Marie Louise Ndzie Noah; Hong Sun

doi:10.3389/fcvm.2021.719805

Isoproterenol-Induced Cardiomyopathy Recovery Intervention: Amlexanox and Forskolin Enhances the Resolution of Catecholamine Stress-Induced Maladaptive Myocardial Remodeling

Front Cardiovasc Med. 2021 Nov 25:8:719805. doi: 10.3389/fcvm.2021.719805. eCollection 2021.

Authors

Affiliations

¹ Department of Physiology, Xuzhou Medical University, Xuzhou, China.
² The College of Biology and Food, Shangqiu Normal University, Shangqiu, China.
³ Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China.
⁴ Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, Albert-Ludwigs University Freiburg, Freiburg, Germany.
⁵ Faculty of Biology, Albert-Ludwigs University Freiburg, Freiburg, Germany.
⁶ The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China.

Abstract

The increasing incidence of stress-induced cardiomyopathy is due to the complexities of our modern-day lives, which constantly elicit stress responses. Herein, we aimed to explore the therapeutic potential of Amlexanox and Forskolin in promoting the recovery from stress-induced cardiomyopathy. Isoproterenol-induced cardiomyopathy (ICM) models were made, and the following treatment interventions were administered: 5% v/v DMSO as a placebo, Amlexanox (2.5 mg/100 g/day) treatment, Forskolin (0.5 mg/100 g/day), and Amlexanox and Forskolin combination, at their respective aforementioned dosages. The effects of Amlexanox and Forskolin treatment on ICM models were assessed by eletrocardiography and echocardiography. Also, using histological analysis and ELISA, their impact on myocardial architecture and inflammation were ascertained. ICM mice had excessive myocardial fibrosis, hypertrophy, and aggravated LVSDs which were accompanied by massive CD86+ inflammatory cells infiltration. Amlexanox treatment attenuated the myocardial hypertrophy, fibrosis, and inflammation and also slightly improved systolic functions. Meanwhile, forskolin treatment resulted in arrhythmias but significantly enhanced the resolution of myocardial fibrosis and inflammation. Intriguingly, Amlexanox and Forskolin combination demonstrated the most potency at promoting the recovery of the ICM from LVSD by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. Our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for enhancing cardiac function recovery from stress-induced cardiomyopathy by promoting the resolution of maladaptive cardiac remodeling.

Keywords: amlexanox; forskolin; isoproterenol-induced cardiomyopathy; left ventricular systolic dysfunction; myocardial fibrosis; myocardial inflammation; stress.