Lin28a-Mediated Metabolic Remodeling in Pathological Cardiac Hypertrophy
Abstract
The proposed project is primarily focusing on addressing cardiomyopathy, an area of encouragement in the Fiscal Year 2018 Peer Reviewed Medical Research Program. Adult heart disease is the leading cause of mortality and morbidity in the United States. Many forms of adult heart disease such as hypertension, ischemic heart disease, and valvular disease are accompanied by pathological cardiac hypertrophy, which is characterized by the thickening of the ventricular myocardium. While the hypertrophic mechanism has been generally regarded as compensatory in conferring resistance to cardiac stress, prolonged hypertrophy predisposes individuals to intractable heart failure. As such, recent basic and preclinical studies suggest that attenuation of pathological hypertrophy has a beneficial effect of mitigating the development of heart failure, making it a promising target for therapeutic interventions. However, cardiac structural remodeling resulted from prolonged cardiac hypertrophy can only be partially reversed by removing the mechanical overload. Under persistent pressure overload, pharmacological agents, such as ACEIs, ARBs, and PDE5A inhibitor, can partially reverse the cardiac structure remodeling. It is consistent with the findings from clinical observations. A meta-analysis shows that the regression of left ventricular mass is about 9.8%-12.5% on average with current treatment. These studies motivate us to further pursue the molecular basis of pathological cardiac hypertrophy, which could have considerable impact for the development of more potent therapeutics for human patients. Importantly, our findings in this study may inspire a new perspective to survey future direction of cardiac hypertrophy treatment. Cardiac hypertrophy is not only an independent risk factor for heart failure and other adverse outcomes, but also shows a grade-dependent relationship with major cardiovascular events, which means patients can receive extra clinical benefits if the regimens bring about any further regression of cardiac hypertrophy. Moreover, reduction of cardiac hypertrophy can reduce the risk of cardiovascular diseases in a blood pressure-independent manner. Since all current agents can reduce blood pressure, novel treatments directly targeting cardiac hypertrophy without lowering blood pressure may provide a new opportunity for combination drug therapy, avoiding drug-associated hypotension side effects. The focus of this proposal is on the role of Lin28a and its downstream mediator Pck2, the mitochondrial phosphoenolpyruvate (PEP) carboxykinase, in promoting cardiomyocyte glycolysis and subsequent cardiac hypertrophic growth. Knowledge regarding the molecular and physiological basis of pathological cardiac hypertrophy has accumulated over the past decades, but still remains limited in the development of novel yet potent remedies. The successful completion of the proposed studies will identify a novel mechanism underlying this detrimental process. Overall, our study 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.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910242
Entities
People
- Jiandong Liu
Organizations
- United States Army
- University of North Carolina at Chapel Hill