Pathological cardiac hypertrophy is a major risk factor of heart failure and sudden cardiac death, the leading cause of mortality in the US and worldwide. Despite substantial progress in our understanding of the molecular and physiological basis of this detrimental process, much remains to be learned. Cardiac hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional, posttranscriptional and epigenetic regulation of the cardiac genome. RNA-binding protein (RBPs) constitutes a major layer of molecular regulation integral to the establishment of tissue transcriptomes. The RBPs play fundamental roles during both development and disease by regulating RNA biogenesis, structure, stability, transport and cellular localization. Among them, Lin28a was found to control many developmental and cellular processes including pluripotency, oncogenesis, tissue repair and metabolism via its role in increasing mRNA stability and/or translation efficiency. Although previous studies have implicated transcriptional factors and signaling molecules in pathological cardiac hypertrophy, the role of RBPs in this process received little attention. Through gene expression analysis, we found that Lin28a exhibited a dynamic expression during early stage of pathological cardiac hypertrophy. Cardiac specific deletion of Lin28a blunted pressure overload-induced cardiac hypertrophy. Likewise, in an in vitro model of cardiac hypertrophy, knockdown of Lin28a attenuated norepinephrine (NE)-induced hypertrophy, while overexpressing Lin28a alone was sufficient to enhance cardiomyocyte glycolysis and stimulate subsequent cardiomyocyte hypertrophic growth. Mechanistically, we found that Lin28a directly bound to the mRNA of Pck2, which encodes the mitochondrial phosphoenolpyruvate carboxykinase, and positively impacted its transcript level. Additionally, manipulation of Pck2 expression phenocopied the metabolic and hypertrophic phenotypes of manipulating Lin28a expression. Based on these observations, we hypothesize that Lin28a and its downstream mediator Pck2 act as crucial regulators of pathological cardiac hypertrophy via their roles in regulating cardiomyocyte metabolism.
The aim of this proposal will leverage our series of unique tools, reagents, and animal models to elucidate the molecular and cellular pathways essential for the development of pathological cardiac hypertrophy. In doing so, we will address a central question concerning whether and how a metabolic switch to a more glycolytic phenotype during cardiac hypertrophy could contribute to the structural remodeling.
Pathological cardiac hypertrophy is a major risk factor for heart failure and sudden cardiac death, the leading cause of death in the US and worldwide. Despite substantial progress in our understanding of the molecular and physiological basis of pathological hypertrophy, it remains limited to bring novel yet potent remedies. This proposal aims to further delineate the regulatory mechanisms underlying pathological hypertrophy to improve understanding of this detrimental process and facilitate the search for treatments.
