# Cell type-specific function of LMNA during myocardial stress in the development of cardiomyopathy

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $406,144

## Abstract

Project Summary
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 LM...

## Key facts

- **NIH application ID:** 9865877
- **Project number:** 1R01HL150019-01
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Jason Cheol Choi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,144
- **Award type:** 1
- **Project period:** 2020-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865877

## Citation

> US National Institutes of Health, RePORTER application 9865877, Cell type-specific function of LMNA during myocardial stress in the development of cardiomyopathy (1R01HL150019-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9865877. Licensed CC0.

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