Developing new treatments for heart disease
Heart disease, the leading cause of death in the United States, is frequently associated with cardiac cell death. Understanding the cell death mechanisms could uncover new drug targets for heart protection.
Adult Mouse Cardiomyocytes (AMCMs)
The long-term research goals of the Cheng lab are to identify novel molecules involved in the regulation of cardiac cell death, including apoptosis, necrosis, and autophagy-dependent cell death. We use biochemical, molecular, cellular, genetic, pathophysiological and histological approaches, to study many types of cardiovascular disorders. Specifically, we are interested in cancer treatment-related cardiotoxicity, myocardial infarction, ischemia/reperfusion injury, cardiac hypertrophy, and heart failure, among others. Our ultimate purpose is to develop new treatments for heart disease.
Adult Mouse Heart Sections
Neonatal Rat Cardiomyocytes (NRCMs, red) and Cardiac Fibroblasts (green)
Cancer treatment-related cardiotoxicity
The anthracycline compounds, widely used in current cancer chemotherapy, can cause irreversible, dose-dependent cardiac injury including cardiomyocyte apoptosis and cardiac atrophy. We show that the anthracycline doxorubicin induces CDK2-dependent FOXO1 activation, which is necessary for both apoptosis and atrophy. Moreover, we identify FOXO1 as a transcription factor for the pro-apoptotic gene Bim and the pro-atrophic gene MuRF1. Using a small molecule FOXO1 inhibitor AS1842856, we show that pharmacological inhibition of FOXO1 attenuates doxorubicin-induced systolic dysfunction, cardiac atrophy, and ventricular remodeling. Our findings, for the first time, establish FOXO1 as a critical mediator of doxorubicin-induced cardiotoxicity. Our study identifies FOXO1 as a potential drug target in anthracycline cardiotoxicity. Small molecule FOXO1 inhibitors, which are currently under clinical development, could represent promising therapeutics for cardiomyopathy and heart failure caused by cancer chemotherapy.
Role of PKA signaling in heart disease
Protein kinase A (PKA) activity is pivotal for proper functioning of the human heart, and its dysregulation has been implicated in a variety of cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by the PRKAR1A gene) is highly expressed in the heart, and controls PKA kinase activity by sequestering PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex in early adulthood, and may die later in life from cardiac complications such as heart failure. We report that left ventricular mass is reduced in young Carney complex patients with PRKAR1A mutations or deletions. Cardiac‐specific heterozygous ablation of PRKAR1A in mice increases cardiac PKA activity, and reduces heart weight and cardiomyocyte size. We further show that PRKAR1A deficiency suppresses cardiomyocyte hypertrophy and impedes heart growth, likely through inhibiting Drp1‐mediated mitochondrial fission. These findings provide a potential novel mechanism for the cardiac manifestations associated with Carney complex.