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Smyd5 Regulates Hypertrophic Growth in the Heart
Author(s) -
Anderson Alexa,
Miller Mickey,
Wang Li,
Franklin Sarah
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.732.12
Subject(s) - heart failure , muscle hypertrophy , heart disease , histone , medicine , heart development , endocrinology , cardiac function curve , knockout mouse , phenotype , biology , fibrosis , epigenetics , gene , genetics , embryonic stem cell
Heart disease is the most financially debilitating and fatal disease between both men and women in the United States. Heart failure is defined as the point at which the heart's ability to function declines, due to overexertion, and can no longer sufficiently pump blood to vital organs throughout the body. While there are different forms of heart disease the pathophysiology of these is largely conserved: the heart compensates for an increased work load by undergoing hypertrophic growth and ultimately progresses onto heart failure. The Smyd family of histone methyltransferases has been studied for their involvement in cell growth during development and disease and is thought to accomplish this by regulating gene expression through histone methylation. While the roles of Smyd1, 2, and 3 are beginning to be defined, the remaining two family members, Smyd4 and 5, are virtually uncharacterized. My hypothesis is that Smyd5 is involved in inhibiting hypertrophic growth in the myocardium, however, its role in the heart is completely unknown. To determine the function of Smyd5, we generated constitutive and inducible, cardiac‐specific Smyd5 knockout mice and have characterized their cardiac phenotype under basal conditions and after stress (pressure‐overload hypertrophy and isoproterenol infusion). When compared to wild type mice, these animals display elevated heart weight/body ratios and left ventricular wall thickening as well as increased fibrosis and changes in fetal gene expression normally detected in cardiac hypertrophy. In addition knockout of Smyd5 significantly reduces methylation of lysine 20 on histone H4, suggesting a mechanistic basis for this phenotype. Together, our results show that although Smyd5 is dispensable for cardiac development, it is a critical regulator of hypertrophic cell growth and pathologic gene expression in the cardiomyocyte and highlights a novel role for this histone methyltransferase in the myocardium. Support or Funding Information ACCESS, BioURP, APS (UGREF), UROP, CVRTI