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.
Highlights
The incidence of cardiovascular diseases (CVDs) keeps increasing due to the enormous amount of risk factors which hastens their progression
A resultant from the demands of our modernday human societies, induces induced cardiomyopathy (ICM), which results in heart failure (HF)
This study aimed to explore the therapeutic potentials of AMLX in attenuating left ventricular systolic dysfunctions (LVSD) and facilitating recovery from ICM, as demonstrated in the acute myocardial infarction (AMI) model [11]
Summary
The incidence of cardiovascular diseases (CVDs) keeps increasing due to the enormous amount of risk factors (sexgender difference, heredity, and unhealthy lifestyles) which hastens their progression. Isoproterenol (an agonist of β1AR and β2AR), besides being used for bradycardia treatment, has been extensively used to mimic catecholamines in modeling chronic stress-induced cardiomyopathy [hereafter referred to as Isoproterenol-induced cardiomyopathy (ICM)] so as to be able to elucidate its underlying pathomechanisms [8, 9]. Despite considerable efforts in elucidating the disease mechanisms of ICM, which have mainly implicated the maladaptive stimuli signal mediation of β2AR [5], very few treatment interventions aimed at attenuation of the pathological cardiac remodeling have been demonstrated in animal models. This study sought to explore if amlexanox (AMLX), which was recently demonstrated to aid in the recovery of cardiac function from AMI, could do the same in ICM models. CAMP is reported to be downregulated in most CVDs [1, 12]; forskolin (FSKN) was utilized as a treatment intervention to ensure its bioavailability and explore the possible therapeutic outcomes
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