Pyridine nucleotide redox potential in coronary smooth muscle couples myocardial blood flow to cardiac metabolism

Marc M. Dwenger, Sean M. Raph, Michelle L. Reyzer, M. Lisa Manier, Daniel W. Riggs, Zachary B. Wohl, Vahagn Ohanyan, Gregory Mack,, Thomas Pucci, Joseph B. Moore, Bradford G. Hill, William M. Chilian, Richard M. Caprioli, Aruni Bhatnagar and Matthew A. Nystoriak ()
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Marc M. Dwenger: Diabetes and Obesity Center, University of Louisville
Sean M. Raph: Diabetes and Obesity Center, University of Louisville
Michelle L. Reyzer: Vanderbilt University School of Medicine
M. Lisa Manier: Vanderbilt University School of Medicine
Daniel W. Riggs: Diabetes and Obesity Center, University of Louisville
Zachary B. Wohl: Diabetes and Obesity Center, University of Louisville
Vahagn Ohanyan: Northeast Ohio Medical University
Gregory Mack,: Northeast Ohio Medical University
Thomas Pucci: Northeast Ohio Medical University
Joseph B. Moore: Diabetes and Obesity Center, University of Louisville
Bradford G. Hill: Diabetes and Obesity Center, University of Louisville
William M. Chilian: Northeast Ohio Medical University
Richard M. Caprioli: Vanderbilt University School of Medicine
Aruni Bhatnagar: Diabetes and Obesity Center, University of Louisville
Matthew A. Nystoriak: Diabetes and Obesity Center, University of Louisville

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Adequate oxygen delivery to the heart during stress is essential for sustaining cardiac function. Acute increases in myocardial oxygen demand evoke coronary vasodilation and enhance perfusion via functional upregulation of smooth muscle voltage-gated K+ (Kv) channels. Because this response is controlled by Kv1 accessory subunits (i.e., Kvβ), which are NAD(P)(H)-dependent aldo-keto reductases, we tested the hypothesis that oxygen demand modifies arterial [NAD(H)]i, and that resultant cytosolic pyridine nucleotide redox state influences Kv1 activity. High-resolution imaging mass spectrometry and live-cell imaging reveal cardiac workload-dependent increases in NADH:NAD+ in intramyocardial arterial myocytes. Intracellular NAD(P)(H) redox ratios reflecting elevated oxygen demand potentiate native coronary Kv1 activity in a Kvβ2-dependent manner. Ablation of Kvβ2 catalysis suppresses redox-dependent increases in Kv1 activity, vasodilation, and the relationship between cardiac workload and myocardial blood flow. Collectively, this work suggests that the pyridine nucleotide sensitivity and enzymatic activity of Kvβ2 controls coronary vasoreactivity and myocardial blood flow during metabolic stress.

Date: 2022
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DOI: 10.1038/s41467-022-29745-z

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