Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.
- 1University of Utah School of Medicine
Abstract
Background: Cardiomyocytes respond to stress by undergoing hypertrophic growth driven by dynamic changes in gene expression. Epigenetic mechanisms, including histone methylation, play critical roles in regulating these transcriptional programs, yet the enzymes controlling these modifications during cardiac disease remain largely unknown. The SMYD family of histone methyltransferases regulates gene expression in multiple biological contexts, but the function of SMYD5 in the mammalian heart has never been investigated. Methods: SMYD5 expression was assessed in human heart failure samples and in a mouse model of cardiac hypertrophy. To define its functional role in vivo, we generated inducible cardiomyocyte-specific Smyd5 knockout mice and characterized their cardiac phenotype using molecular, histological, and functional analyses. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was performed to examine histone H4 lysine 20 trimethylation (H4K20me3) at the Il-6 promoter. Results: SMYD5 expression was altered in diseased human and mouse hearts. Under basal conditions, cardiomyocyte-specific deletion of Smyd5 resulted in baseline structural cardiac remodeling and transcriptional signatures characteristic of pathological stress. Smyd5-deficient hearts exhibited marked inflammatory activation resembling a cytokine storm with immune cell infiltration and heart failure. Notably, Smyd5 knockout mice displayed a 100-fold increase in Il-6 expression, accompanied by a global reduction in H4K20me3. ChIP-qPCR analysis of the Il-6 promoter, together with loss- and gain-of-function analysis of SMYD5, supports a direct epigenetic role of SMYD5 in regulating Il-6 expression through H4K20me3 in cardiomyocytes. Conclusions: SMYD5 is a previously unrecognized epigenetic regulator of cardiac homeostasis that restrains inflammatory signaling in cardiomyocytes under normal conditions. Loss of Smyd5 disrupts H4K20me3, leading to derepression of Il-6 in cardiomyocytes and a robust inflammatory response characterized by immune cell recruitment and fibrosis, accompanied by rapid progression of cardiac remodeling and heart failure. These findings identify SMYD5 as a critical regulator of intrinsic cardiomyocyte inflammatory signaling and reveal a novel chromatin-based mechanism contributing to inflammatory cardiomyopathies.
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BibTeX
@misc{bia2026cardiomyocytespecific,
title = {{Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.}},
author = {R. Bia and S. M. Hickenlooper and M. R. Miller and C. C. Li and E. Horiuchi and A. Bakhtina and L. Wang and S. Valdez and K. Davis and A. Anderson and J. Garcia-Llana and L. Farese and S. O'Very and N. Santa Ana and A. Jacobsen and K. Dellerman and C. Gwynn and J. Durrant and J. R. Visker and C. P. Kyriakopoulos and K. Sideris and S. G. Drakos and M. W. Szulik and E. B. Thorp and S. T. Smale and S. Franklin},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.748923},
url = {https://www.biorxiv.org/content/10.64898/2026.09.02.748923v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.
AU - R. Bia
AU - S. M. Hickenlooper
AU - M. R. Miller
AU - C. C. Li
AU - E. Horiuchi
AU - A. Bakhtina
AU - L. Wang
AU - S. Valdez
AU - K. Davis
AU - A. Anderson
AU - J. Garcia-Llana
AU - L. Farese
AU - S. O'Very
AU - N. Santa Ana
AU - A. Jacobsen
AU - K. Dellerman
AU - C. Gwynn
AU - J. Durrant
AU - J. R. Visker
AU - C. P. Kyriakopoulos
AU - K. Sideris
AU - S. G. Drakos
AU - M. W. Szulik
AU - E. B. Thorp
AU - S. T. Smale
AU - S. Franklin
PY - 2026
DA - 2026/09/02
PB - bioRxiv
DO - 10.64898/2026.09.02.748923
UR - https://www.biorxiv.org/content/10.64898/2026.09.02.748923v1
AB - Background: Cardiomyocytes respond to stress by undergoing hypertrophic growth driven by dynamic changes in gene expression. Epigenetic mechanisms, including histone methylation, play critical roles in regulating these transcriptional programs, yet the enzymes controlling these modifications during cardiac disease remain largely unknown. The SMYD family of histone methyltransferases regulates gene expression in multiple biological contexts, but the function of SMYD5 in the mammalian heart has never been investigated. Methods: SMYD5 expression was assessed in human heart failure samples and in a mouse model of cardiac hypertrophy. To define its functional role in vivo, we generated inducible cardiomyocyte-specific Smyd5 knockout mice and characterized their cardiac phenotype using molecular, histological, and functional analyses. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was performed to examine histone H4 lysine 20 trimethylation (H4K20me3) at the Il-6 promoter. Results: SMYD5 expression was altered in diseased human and mouse hearts. Under basal conditions, cardiomyocyte-specific deletion of Smyd5 resulted in baseline structural cardiac remodeling and transcriptional signatures characteristic of pathological stress. Smyd5-deficient hearts exhibited marked inflammatory activation resembling a cytokine storm with immune cell infiltration and heart failure. Notably, Smyd5 knockout mice displayed a 100-fold increase in Il-6 expression, accompanied by a global reduction in H4K20me3. ChIP-qPCR analysis of the Il-6 promoter, together with loss- and gain-of-function analysis of SMYD5, supports a direct epigenetic role of SMYD5 in regulating Il-6 expression through H4K20me3 in cardiomyocytes. Conclusions: SMYD5 is a previously unrecognized epigenetic regulator of cardiac homeostasis that restrains inflammatory signaling in cardiomyocytes under normal conditions. Loss of Smyd5 disrupts H4K20me3, leading to derepression of Il-6 in cardiomyocytes and a robust inflammatory response characterized by immune cell recruitment and fibrosis, accompanied by rapid progression of cardiac remodeling and heart failure. These findings identify SMYD5 as a critical regulator of intrinsic cardiomyocyte inflammatory signaling and reveal a novel chromatin-based mechanism contributing to inflammatory cardiomyopathies.
ER -