The methyltransferase Smyd1 regulates cardiac physiology

PROJECT SUMMARY Coronary artery disease is the leading cause of death in the US and is the primary cause of chronic heart failure. For patients with coronary artery disease, some advancements have been made clinically to restore blood flow in diseased arteries and reduce myocardial injury from the resulting ischemia and subsequent reperfusion. However, even with these advancements one quarter of patients will die or develop heart failure within 1 year. Damage to the myocardium during ischemic injury includes deficiencies in metabolism and energetics. Some key epigenetic regulators can prevent or reduce ischemic injury and pathological remodeling in murine models, however, their ubiquitous expression has made them unsuitable for therapeutic targeting in humans, thus far. In contrast, we recently identified the only known myocyte-specific epigenetic regulator of mitochondrial energetics and metabolism – the histone lysine methyltransferase Smyd1 – which holds great therapeutic potential given its tissue-specific expression. Specifically, we performed the first analysis of Smyd1 function in the adult myocardium using inducible, cardiomyocyte-specific Smyd1 knockout mice and showed that loss of Smyd1 leads to dysregulated cardiac metabolism and suppressed mitochondrial respiration, ultimately leading to heart failure (published in AJP). Subsequently we showed that down-regulation of mitochondrial energetics is an early event in these knockout mice (occurring before the onset of cardiac dysfunction) and results, at least in part, from Smyd1’s regulation of PGC-1α transcription (published in PNAS). To further understand Smyd1’s role in regulating cardiac physiology we recently generated transgenic mice allowing inducible, cardiomyocyte-specific overexpression of the Smyd1a isoform (the mouse ortholog to human SMYD1) and subjected these mice to permanent occlusion of the LAD. Our unpublished preliminary results show that Smyd1a gain-of-function can enhance mitochondrial respiration and protect from ischemic injury, although how this is accomplished molecularly is unknown. In addition, our preliminary data from these mice show increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae, concomitant with increased Opa1 expression, a known driver of cristae morphology. These results implicate Opa1 as a novel, functionally important downstream target of Smyd1a whereby cardiomyocytes upregulate energy efficiency, protecting them from ischemic injury. Our overarching hypothesis is that Smyd1a protects from ischemic injury by regulating mitochondrial energetics and enhancing respiration efficiency in the cardiomyocyte through regulation of both: 1) PGC-1α expression (a regulator of electron transport chain gene expression) and 2) OPA1-mediated cristae remodeling and stabilization of electron transport chain supercomplexes. We will test this hypothesis in our transgenic mice which conditionally overexpress Smyd1a. In addition, we will examine these pathways in cells and human tissue with a putative SMYD1 loss-of-function variant, N101S, which we identified with collaborators at the U. of Pittsburgh (Dr Lina Gonzalez) in a patient with hypertrophic cardiomyopathy and heart failure.