Abstract 730: Celltype-Specific Functions in Dilated Cardiomyopathy Caused by the LMNA Gene Mutation

Abstract

Mutations in the LMNA gene, encoding lamins A and C (lamin A/C) cause a diverse group of human diseases termed laminopathies. The most prevalent laminopathy is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) characterized by variable onset of fibrosis/pathological remodeling that always progresses to heart failure. Despite recent progress, how cell type-specific effects of LMNA mutations are integrated at the tissue level to engender complex pathologies in a heterocellular organ such as the heart are not well understood. Using a conditional deletion model that permits cardiomyocyte (CM)-specific Lmna deletion coupled with translating ribosome affinity purification, we found that CM-specific lamin A/C depletion caused rapid fibrosis and severe cardiac dysfunction accompanied by endoplasmic reticulum (ER) stress. At the molecular level, CM-specific translating mRNA profiling identified increased expression of MED25, a member of the Mediator complex implicated in regulating ER stress responses, prior to the onset of cardiac dysfunction. In contrast, lamin A/C depletion selectively in cardiac fibroblasts (CFs) displayed no immediate cardiac pathology whereas a concurrent depletion in both CMs and CFs resulted in lesser fibrosis and pathological remodeling. These results suggest that lamin A/C play an important role in CF biology and that reactive CFs underlie the rapid onset and the exaggerated LMNA cardiomyopathy symptoms observed in mice with CM-only Lmna deletion. Mechanistically, we found that increased matrix stiffness elevated the expression of MED25 and ER stress markers in lamin A/C-depleted CMs in vitro , indicating that the physical component of fibrosis may underlie the observed molecular changes. Taken together, our results suggest lamin A/C-depleted CFs mediate a brake on cardiomyopathy development and interactions between CFs and CMs are important determinants of the rate of progression and the severity of LMNA cardiomyopathy. Therefore, strategies targeting lamin A/C function in CFs may hold therapeutic potential for patients with LMNA cardiomyopathy as well as for other forms of cardiomyopathy in which fibrosis is integral to disease pathogenesis.