Exercise Training and Ventricular Remodeling in the Mouse : Effects of Adenosine and Matrix Metalloproteinases

Coordinating Institution: CRP Sante
Contracting Partner(s): Universitätsklinik Homburg
From: 01/11/2007
To: 30/04/2010
Budget: 127,500.00€
Contact(s): Wagner Daniel R.

Summary

Despite modern reperfusion therapies, the number of deaths from heart failure (HF) following myocardial infarction (MI) still continues to increase in developed countries such as Luxembourg. Left ventricular remodeling, characterized by an unfavorable reshaping of the heart after myocardial injury and cardiomyocytes hypertrophy, represents the main mechanism setting the stage for the development of HF. Adenosine, a small cardioprotective nucleoside, is produced in large amounts in the ischemic heart and has been proposed to inhibit cardiac remodeling after MI. Physiological hypertrophy of the heart induced by physical activity provides protection from HF.

Since adenosine levels are also increased in the heart after physical activity, we hypothesized that adenosine may participate in the protective effects of physiological hypertrophy on left ventricular remodeling. We first characterized the role and the regulation of adenosine receptors in the hypertrophic response induced by phenylephrine (PE) in isolated neonatal rat cardiomyocytes. We have characterized the effects of adenosine A1 receptor on PE-induced hypertrophy through assessment of the reactivation of the fetal gene program (β-MHC, ANF), expression of the immediate early gene c-fos, cardiomyocyte diameter and sarcomeric organization.

While we had shown in 2008 that PE treatment increased the expression of the adenosine A1 receptor and induced the reactivation of the fetal gene program, we have now shown that PE significantly induced c-fos expression and increased cardiomyocyte diameter and sarcomeric organization. This early cellular response could be significantly reduced by treatment with the selective A1 receptor agonist CPA. In contrast, inhibition of the adenosine A1-receptor with the selective A1 receptor antagonist DPCPX increased the PE-mediated effects.

These results show that activation of the A1 adenosine receptor inhibits the PE-induced maladaptive myocardial hypertrophic response. Ongoing experiments aim at testing the impact of 6 weeks of voluntary physical activity on left ventricular remodeling assessed 6-12 weeks after myocardial infarction using a mouse model. Remodeling is characterized by functional (echocardiography; high fidelity pressure catheter), histological (heart weight/body weight ratio; heart weight/tibia length; weight of lungs, kidney, liver; cardiomyocyte cross sectional area, determination of fibrosis), and biochemical (activation of the PI3K/Akt signaling pathway, gene expression of molecular markers of cardiac hypertrophy) analyses.