Abstract P3098: Immune Suppression Ameliorates A Mouse Model Of Lmna-related Cardiomyopathy With Nuclear Envelope Rupture

Abstract

Lamin A/C (encoded by the LMNA gene) are the components of the nuclear lamina, a protein meshwork providing the structural integrity to the nuclear membrane. Dilated cardiomyopathy (DCM) caused by LNNA gene mutations is the second most common familial DCM in adults and associated with severe prognosis and high mortality. Despite decades of investigations into cell autonomous impacts of LMNA mutations, LMNA-DCM lacks effective treatments except for heart transplantation. Here, we identify cell non-autonomous effects of LMNA mutations and demonstrate the efficacy of targeting immune activities in mouse models of LMNA-DCM. We induced Lmna gene deletion specifically in cardiomyocytes in adult mice and tracked molecular, cellular, and physiological alterations in the heart at a high temporal resolution. We identified frequent localized nuclear envelope rupture, with the concomitant exposure of nuclear DNA to the cytoplasm, as the earliest direct consequence of Lamin A/C protein reduction in cardiomyocytes. Surprisingly, nuclear envelope rupture did accompany cardiomyocyte cell death or extensive transcriptional changes or cytosolic DNA sensing pathway activation within the cardiomyocytes. Instead, it coincided with extensive proinflammatory signaling activation within the cardiac macrophage population. This was followed by extensive fibrosis and structural and functional alterations of the heart, culminating in DCM and death. Treatment of LMNA-DCM mice with the immunosuppressant Dexamethasone suppressed fibrosis, profoundly improved the cardiac structure and function, and conferred a two-fold lifespan extension after Lmna gene deletion. This work suggested that immune activation is the major pathological component of LMNA-DCM and an effective target for treating LMNA-DCM patients.