Cardiac hypertrophy is associated with diastolic dysfunction, slowed relaxation, and reduced ejection. Its presence serves as an independent risk factor for myocardial infarction, congestive heart failure, and sudden death. While changes in cellular Ca2+ handling have been linked to these derangements, both a reduced contractile relaxation rate and Ca2+ transport rate may be associated with altered cardiac energetics and metabolic activity. This study will examine the possibility for a causal link between the molecular changes in Ca2+ handling and the metabolic changes within the mitochondria (MITO). 13C and 31P NMR methods will be used to follow the metabolic response of hypertrophic rat heart under conditions of stress and injury. These conditions are characterized by moderate and high increases in Ca2* load. We hypothesize that (1) high MITO [Ca2+] plays a key role in uncoupling metabolic activity from workload, (2) the specific mechanisms involved are dependent on Ca2+ load, and (3) metabolic uncoupling can be reversed by enhancing Ca2+ handling via the over-expression of SERCA protein. Importantly, recent reports indicate that the over-expression of SERCA in hypertrophic heart by adenoviral gene transfer results in enhanced Ca2+ handling and restored contractility. However, the metabolic response of the heart to this treatment has not been fully characterized, and it is not know if energy production or function can be sustained for increased contractility.
The specific aims are: (1) determine if MITO Ca2* load increases parallel to cytosolic Ca2+ in hypertrophy under conditions of stress (beta-adrenergic stimulation) and injury (post-ischemic reperfusion), (2) determine whether the opening of the Ca2+ sensitive MITO permeability transition pore (MPT) is greater for hypertrophic heart following injury, parallel to increased metabolic uncoupling, (3) determine whether the activity of two key regulators of MITO metabolism (PDH and alphaKGDH) are responsive to changes in Ca2+ load with hypertrophy, and (4) determine if enhancing calcium handling, via the over-expression of SERCA by in vivo gene transfer, (a) alters MITO Ca2+, (b) influences the activity of MPT, PDH, and alphaKGDH and thereby (c) enhances metabolic coupling to workload. Our long term goal is: to identify the specific mechanisms of metabolic uncoupling in hypertrophic heart as potential targets for therapeutic intervention.
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