The overarching aim of this proposal is to elucidate vascular effectors that transduce metabolic signals that enable the connection of flow to cardiac metabolism-metabolic dilation. The heart is dependent on metabolic dilation for aerobic energy production because anaerobic reserve is virtually non-existent;however, the effectors responsible for coupling flow to metabolism in the heart remain unidentified. The matching of flow to metabolism is important and may play a role in microvascular diseases in the heart. We have suggested that Kv channels transduce the H2O2 metabolic signal into redox- mediated coronary metabolic vasodilation. Because certain members of the Kv1 family of channels are redox sensitive (e.g., Kv1.2, 1.3 and 1.5), our first goal will determine, which redox sensing Kv channels transduce metabolic signals to flow in the heart.
This aim will be tested using loss and gain of function approaches. Loss of function will use mice null for Kv1.5 and 1.3 channels, and heterozygous null for Kv1.2 channels (Kv1.2-/- is lethal), and gain of function will study of expression of the specific ion channel using a smooth muscle specific Tet On system driving expression of the Kv channel. We have found that metabolic dilation in the diabetic db/db mouse is impaired and that expression of Kv1.2, 1.3, and 1.5 channels is substantially decreased in arteries of these mice. Our goal in the second aim is to perform gain of function studies in db/db mice by expressing Kv1.5, 1.2 and/or Kv1.3 channels using the Tet inducible system in smooth muscle. Our overall strategy is to measure the relationship between cardiac work, and myocardial blood flow and tissue oxygenation along with evaluating measures of cardiac function and myocardial ischemia. We also will perform in vitro studies to determine the production of vasoactive metabolites from cardiac myocytes, vascular reactivity of isolated arterioles and electrophysiological parameters in smooth muscle. This integrated approach-from electrophysiology to in vivo flow regulation should enable answers regarding basic coronary physiology and flow regulation, as well as potential therapies for diabetic cardiomyopathy.
Clinical trials have found the occurrence of myocardial ischemia in patients who do not have coronary disease, which is generalized as coronary microvascular dysfunction. Our application addresses impairments in the regulation of blood flow in microvessels of the heart as an underlying cause of this coronary microvascular dysfunction.
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