# The Role of CAP2 In Sex-Related Myocardial Function

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $402,500

## Abstract

Summary
Sudden cardiac death kills 180,000 to 450,000 Americans annually. In patients without coronary artery
disease, the highest risk of sudden death is in those with cardiomyopathy and intraventricular
conduction delay. Furthermore, males experience sudden death almost three times more frequently
than females and the reasons for this sex bias are unclear. Identifying the mechanisms underlying
cardiomyopathy and conduction disorders may improve screening for patients at risk for sudden death,
or outcomes of those revived from cardiac arrest. To date, most known mutations that cause
cardiomyopathy are in sarcomere cytoskeletal proteins whereas most familial cardiac conduction
diseases (CCD) are caused by mutations in ion channels or channel interacting proteins. However,
mutations in cytoskeletal proteins can also cause CCD but the mechanisms linking the cytoskeleton to
CCD are not well understood. There is a gene or genes on chromosome 6 (6p22) associated with
sudden cardiac death near the cytoskeletal protein CAP2 (Cyclase Associated Protein 2). CAPs are
widely conserved cytoskeleton proteins. We first identified CAP in yeast as an adenylyl cyclase binding
protein. Additionally, all CAP homologs are actin monomer binding proteins that regulate the balance
between actin filaments and actin monomers. Mammals have two CAP isoforms, CAP1 and CAP2. To
determine the function of CAP2 in vivo we generated CAP2 knockout (CAP2-KO) mice, both whole
body and conditional. Our preliminary data show that whole body CAP2-KO mice are born alive, but
many die suddenly shortly after birth, with only ~30% of male CAP2-KO surviving beyond 12 weeks.
CAP2-KO mice develop CCD with mild dilated cardiomyopathy (DCM). The conduction phenotypes are
more penetrant in cardiomyocyte-specific CAP2-KO mice, with all mice dying of complete heart block
by 25 weeks. Furthermore, genome-wide analysis revealed that several transcriptional networks,
including the serum response factor (SRF) network, were upregulated in the hearts of CAP2-KO mice.
Based on these findings we hypothesize CAP2 maintains cardiac conduction by modulating
SRF signals and fibrotic responses in a sex-specific manner. These studies are relevant to
understanding the role of the cytoskeleton and gender specificity in cardiac conduction and sudden
cardiac death. To test this hypothesis, we propose the following specific aims:
To test this hypothesis, we propose to (1) Determine the specific role of CAP2 in the cardiac
conduction system (2) Determine the role of CAP2 in serum response factor (SRF) signaling, and (3)
Determine the role of Secreted Frizzled-related protein 2 in sex-specific sudden cardiac death in CAP2
mice.

## Key facts

- **NIH application ID:** 9838780
- **Project number:** 5R01HL134923-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JEFFREY M FIELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2016-12-12 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838780

## Citation

> US National Institutes of Health, RePORTER application 9838780, The Role of CAP2 In Sex-Related Myocardial Function (5R01HL134923-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838780. Licensed CC0.

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