Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis
Open Access
- 1 October 2020
- journal article
- research article
- Published by Wiley in ESC Heart Failure
- Vol. 7 (5), 2838-2852
- https://doi.org/10.1002/ehf2.12887
Abstract
Aims Left ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long-time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)-induced myocarditis. Methods and results SWR/J mice were infected with 5 x 10(4) plaque-forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8-fold (P < 0.05), 1.4-fold (P < 0.05), 3.2-fold (P < 0.01), and 2.1-fold (P < 0.001) reduction in LV intercellular adhesion molecule 1 expression, presence of monocytes/macrophages, oxidative stress, and apoptosis, respectively, was observed in eplerenone-treated vs. untreated CVB3-infected mice. in vitro, eplerenone led to 1.4-fold (P < 0.01) and 1.2-fold (P < 0.01) less CVB3-induced cardiomyocyte oxidative stress and apoptosis. Furthermore, collagen production was 1.1-fold (P < 0.05) decreased in cardiac fibroblasts cultured with medium of eplerenone-treated vs. untreated CVB3-infected HL-1 cardiomyocytes. These ameliorations were in vivo translated into prevention of cardiac fibrosis, as shown by 1.4-fold (P < 0.01) and 2.1-fold (P < 0.001) lower collagen content in the LV of eplerenone-treated vs. untreated CVB3-infected mice at Days 8 and 28, respectively. This resulted in an early and long-lasting improvement of LV dimension and function, as indicated by reduced LV end-systolic volume and end-diastolic volume, and an increase in LV contractility (dP/dt(max)) and LV relaxation (dP/dt(min)), respectively (P < 0.05). Conclusions Early intervention with the MRA eplerenone modulates the acute host and defence reaction and prevents cardiac disease progression in experimental CVB3-induced myocarditis without aggravation of viral load. The findings advocate for an initiation of therapy of viral myocarditis as early as possible, even before the onset of inflammation-induced myocardial dysfunction. This may also have implications for coronavirus disease-19 therapy.Funding Information
- Pfizer
- Deutsche Forschungsgemeinschaft (SFB Transregio 19 A2)
This publication has 71 references indexed in Scilit:
- Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac FibrosisHypertension, 2012
- Mesenchymal Stromal Cells but Not Cardiac Fibroblasts Exert Beneficial Systemic Immunomodulatory Effects in Experimental MyocarditisPLOS ONE, 2012
- Reduced Degradation of the Chemokine MCP-3 by Matrix Metalloproteinase-2 Exacerbates Myocardial Inflammation in Experimental Viral CardiomyopathyCirculation, 2011
- Mesenchymal Stem Cells and Inflammatory Cardiomyopathy: Cardiac Homing and BeyondCardiology Research and Practice, 2011
- Sex‐Specific Impact of Aldosterone Receptor Antagonism on Ventricular Remodeling and Gene Expression after Myocardial InfarctionClinical and Translational Science, 2009
- Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral MyocarditisCirculation, 2006
- Myocardial proteases and matrix remodeling in inflammatory heart diseaseCardiovascular Research, 2006
- Aldosterone Stimulates Matrix Metalloproteinases and Reactive Oxygen Species in Adult Rat Ventricular CardiomyocytesHypertension, 2005
- Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein geneThe FASEB Journal, 2004
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001