Mutations in the LMNA gene encoding 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). Despite recent progress in understanding the diverse cellular function of lamin A/C, what pathogenic mechanisms are triggered by LMNA mutations in specific cell types of the myocardium and how they are integrated at the tissue level to produce a cardiac phenotype is largely unknown. The prevailing view is that LMNA mutations cause a myriad of cellular defects that all contribute to the disease but this broad assertion has never been rigorously tested. Our preliminary data suggest that lamin A/C play a crucial role in cardiac fibroblasts (CF) function in fibrosis and the onset and/or the pathogenicity of LMNA cardiomyopathy is more severe if the lamin A/C function is selectively impaired in cardiomyocytes (CM). In vivo Lmna deletion specifically in adult CMs caused rapid onset of fibrosis and severe cardiac dysfunction. In contrast, Lmna deletion in CFs displayed no immediate cardiac pathology. Surprisingly, relative to CM-deletion alone, concomitant deletion of Lmna in CMs and CFs resulted in lesser fibrosis and pathological remodeling. These results suggest that lamin A/C in CFs play a crucial role in the development of fibrosis/cardiac remodeling and that these pathological features underlie the disease progression and severity in response to CM stress. At the molecular level, we implicate increased matrix stiffness from fibrosis contribute to CM expression of ER stress markers and MED25, which is a member of the Mediator complex identified as a regulator of ER stress responses. 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. Based on our preliminary data, we hypothesize that lamin A/C contribute to the pathogenesis of LMNA cardiomyopathy in an opposing manner depending on the cell type; lamin A/C promote CF-mediated fibrosis in response to myocardial stress while in parallel protect CMs from ER stress and cell damage. To test our hypothesis, Aim1 will determine whether lamin A/C regulation of CF function underlies the rate and the severity of disease progression. We will elucidate the putative mechanisms by which Lmna deletion impairs CF function in the stressed myocardium.
In Aim2, we will determine how the mechanical component of fibrosis contributes to CM damage caused by LMNA mutations. Under varying matrix stiffness, we will delineate the mechanism underlying CM damage caused by LMNA mutations and contextualize the involvement of ER stress.
These aims will not only lead to a better understanding of lamin A/C function in CFs, CMs, and their crosstalk in disease pathogenesis but may also enable the development of new therapies for LMNA cardiomyopathy and perhaps other forms of cardiomyopathies in which fibrosis is integral to their pathogenesis.

Public Health Relevance

The proposed research is relevant to public health because it will not only reveal cell type specific molecular insights into how LMNA mutation causes dilated cardiomyopathy and fibrosis, but also serve as a foundation for developing urgently needed new therapies that aim to improve heart function for this life-threatening disease. Due to our studies using novel approaches, the gained insights will also serve as a model for designing new treatments for cardiac fibrosis, which is a well-recognized feature of many forms of cardiomyopathies. Therefore, the proposed study is relevant to the mission of NIH as it will expand fundamental knowledge that will reduce the burden of human illness.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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