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Biological/Clinical Applications 3

PI: Gregg Semenza             Collaborator: Akhilesh Pandey

Regulation of HIF-1alpha  in HF 

A common feature of HF is the reprogramming of cardiac energy metabolism. In the healthy heart, fatty acids are taken up and oxidized in the mitochondria to generate ATP. In HF, fatty acid uptake is reduced and the fatty acids that are taken up are converted to lipid, accumulation of which may have deleterious effects on cardiac function (“lipotoxicity”). Glucose uptake is greatly increased and converted to lactate, i.e. cardiac metabolism switches from respiration to glycolysis, with an attendant decreased production of ATP, which may become limiting for cardiac contractile function. The balance between mitochondrial and glycolytic metabolism is controlled by hypoxia-inducible factor 1alpha (HIF-1alpha). HIF-1alpha is a transcription factor that plays a central role in the response of myocytes. HIF-1 is a critical mediator of adaptive responses to myocardial ischemia  and myocardial preconditioning.  However, little is known about the role of HIF-1alpha in HF. HIF-1alpha is regulated by multiple PTMs, including hydroxylation (Pro and Asn), phosphorylation, S-nitrosylation, sumoylation, and ubiquitylation which control its interactions with other proteins.

Overall Research Goal: To elucidate the exact PTM status and interactome of HIF-1alpha (and each of its splice variants) in heart and how these are modified by hypertrophic signals and, in turn, how modified HIF-1alpha affects the myocardial proteome in HF.

Goal 1:  Analysis of HIF-1alpha alterations and resulting HIF-1alpha dependent protein-based changes in response to hypertrophic signals in cultured neonatal cardiomyocytes.

Rationale:  HIF-1alpha is a key protein in the heart’s response to stress and qualitative (PTMs, alternative isoforms) and/or quantitative changes in HIF-1alpha will occur in response to hypertrophy signals and/or HF.

Goal 2: Analysis HIF-1alpha  influence on cardiac energy metabolism.

Rationale: A final common pathway in HF is a switch from oxidative metabolism of fatty acids to glycolytic metabolism of glucose, with fatty acids used to synthesize lipid. This results in a defect in ATP production that has been proposed to be a major contributing factor to the loss of cardiac contractility. In addition, lipotoxicity may also contribute to end-stage HF pathogenesis.

Goal 3:  Analysis of HIF-1alpha structure and function in human HF.

Rationale: The ultimate goal is to understand the role of HIF-1alpha in human HF. We will perform a proteomic analysis focused on HIF-1alpha to identify changes in PTMs, protein isoforms, and interactome by comparing normal, "non-systolic HF" and dilated HF human hearts.