Abstract 323: Growth Differentiation Factor-15 Is Upregulated in Profibrotic States of Dilated Cardiomyopathy and Not Hypertrophic Cardiomyopathy
Introduction: Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are leading causes of morbidity and mortality in the adult population. Both DCM and HCM arise from structural perturbations and remodeling of the heart, and many cases have been found to result from underlying familial mutations. The signaling pathways by which these mutations lead to pathological ventricular remodeling, fibrosis, and heart failure remain unknown.
Methods: In this study we attempt to identify molecular pathways in a DCM mouse model and compare and contrast the results with those previously observed in HCM mouse models. We use a transgenic mouse expressing an arginine-to-cysteine (R9C) mutation in phospholamban (PLN), previously identified in DCM patients. To define molecules involved in disease progression, we generated expression profiles using high-throughput sequencing and assessed genes of interest by immunostaining.
Results:PLNR9C/+ hearts exhibit increasing fibrosis, with proliferation of non-myocyte cells occurring throughout the disease spectrum. Losartan treatment, which effectively blocks the HCM phenotype, does not block the emergence of DCM and neither reduces fibrosis nor increases lifespan in PLNR9C/+ mice. Growth differentiation factor-15 (GDF15) RNA and protein levels are significantly upregulated in the left ventricles of PLNR9C/+ mice during DCM and heart failure. GDF15 is predominantly expressed in non-myocytes in WT mice, but in PLNR9C/+ mice, is upregulated almost 25-fold in myocytes and less than 1.5-fold in non-myocytes.
Conclusion: Both fibrosis and the proliferation of non-myocytes in PLNR9C/+ mouse hearts increase as the DCM phenotype worsens, similar to that observed in HCM mouse models. However, losartan has no effect on the DCM phenotype suggesting that the molecular pathways of DCM and HCM may be different. This study identifies GDF15 as a signaling molecule that may play a unique role in DCM. GDF15 is upregulated in myocytes during DCM, but remains relatively unchanged in HCM. Understanding the genetic mechanisms underlying the progression of disease and fibrosis in both DCM and HCM will help us to characterize the distinct pathways of both diseases, as well as identify new, more specific targets for therapy.
- © 2012 by American Heart Association, Inc.