Abstract
Chronic catecholamine stress (CCS) induces the occurrence of cardiomyopathy—pathological cardiac hypertrophy (PCH), which is characterized by left ventricular systolic dysfunction (LVSD). Recently, mounting evidence has implicated myocardial inflammation in the exacerbation of pathological cardiac remodeling. However, there are currently no well-defined treatment interventions or regimes targeted at both the attenuation of maladaptive myocardial hypertrophy and inflammation during CCS to prevent PCH. G protein-coupled receptor kinase 5 (GRK5) and adenylyl cyclases (ACs)-cAMP mediates both cardiac and inflammatory responses. Also, GRK5 and ACs are implicated in stress-induced LVSD. Herein, we aimed at preventing PCH during CCS via modulating adaptive cardiac and inflammatory responses by inhibiting GRK5 and/or stimulating ACs. Isoproterenol-induced cardiomyopathy (ICM) was modeled using 0.5 mg/100 g/day isoproterenol injections for 40 days. Alterations in cardiac and inflammatory responses were assessed from the myocardia. Similarities in the immunogenicity of cardiac troponin I (cTnI) and lipopolysaccharide under CCS were assessed, and Amlexanox (35 μM/ml) and/or Forskolin (10 μM/ml) were then employed in vitro to modulate adaptive inflammatory responses by inhibiting GRK5 or activating ACs-cAMP, respectively. Subsequently, Amlexanox (2.5 mg/100 g/day) and/or Forskolin (0.5 mg/100 g/day) were then translated into in vivo during CCS to modulate adaptive cardiac and inflammatory responses. The effects of Amlexanox and Forskolin on regulating myocardial systolic functions and inflammatory responses during CCS were ascertained afterward. PCH mice had excessive myocardial hypertrophy, fibrosis, and aggravated LVSD, which were accompanied by massive CD68+ inflammatory cell infiltrations. In vitro, Forskolin-AC/cAMP was effective than Amlexanox-GRK5 at downregulating proinflammatory responses during stress; nonetheless, Amlexanox and Forskolin combination demonstrated the most efficacy in modulating adaptive inflammatory responses. Individually, the translated Amlexanox and Forskolin treatment interventions were ineffective at subduing the pathological remodeling and sustaining cardiac function during CCS. However, their combination was potent at preventing LVSD during CCS by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. The treatment intervention attained its potency mainly via Forskolin-ACs/cAMP-mediated modulation of cardiac and inflammatory responses, coupled with Amlexanox inhibition of GRK5 mediated maladaptive cascades. Taken together, our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for preventing the occurrence of pathological cardiac hypertrophy during chronic stress.
Highlights
The elevated level of circulating catecholamines during chronic stress is a hallmark for the initiation of adverse remodeling of the left ventricular (LV) (Frey et al, 2004; Liu et al, 2015; Zhang et al, 2019)
Analysis of mRNAs and protein expressions demonstrated that crucial cardiac and inflammatory proteins were altered in the myocardia during catecholamine stress (CCS) compared with under physiological states. betaadrenergic receptors (βAR), AC5, and AC7 were found depleting, while AC6, β-ARR-1, β-ARR-2, GRK2, and G protein-coupled receptor kinases 5 (GRK5) were upregulated in the pathological cardiac hypertrophy (PCH) mice hearts (Supplementary Figures 2A–K)
Cardiac hypertrophy was evident in PCH mice as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were significantly upregulated in their myocardia than Ctrl and Vhl mice (Supplementary Figures 2A,J,K)
Summary
The elevated level of circulating catecholamines during chronic stress is a hallmark for the initiation of adverse remodeling of the left ventricular (LV) (Frey et al, 2004; Liu et al, 2015; Zhang et al, 2019). The progression in LV remodeling has been demonstrated to result in irreversible pathological cardiac hypertrophy (PCH) if there are no timely preventive measures to subdue the excessive firing of neurohormonal stimuli during chronic stress (Schaeuble et al, 2019; Zhang et al, 2019). Irreversible hypertrophic cardiomyopathy has been associated with LV systolic dysfunction (LVSD) (Marstrand et al, 2020). An enormous amount of cardiomyocyte deaths (via both apoptosis and necrosis) occur during chronic catecholamine stress (CCS) (Whelan et al, 2010; Liu et al, 2015). The apoptotic myocyte directly induces fibrosis (Liu et al, 2015), while troponins released from the necrotic cardiomyocytes serve as a damage-associated
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