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- Title
Pyridine nucleotide redox potential in coronary smooth muscle couples myocardial blood flow to cardiac metabolism.
- Authors
Dwenger, Marc M.; Raph, Sean M.; Reyzer, Michelle L.; Lisa Manier, M.; Riggs, Daniel W.; Wohl, Zachary B.; Ohanyan, Vahagn; Mack, Gregory; Pucci, Thomas; Moore IV, Joseph B.; Hill, Bradford G.; Chilian, William M.; Caprioli, Richard M.; Bhatnagar, Aruni; Nystoriak, Matthew A.
- 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. Physiological matching of blood flow to the demand for oxygen by the heart is required for sustained cardiac health, yet the underlying mechanisms are obscure. Here, the authors report a key role for acute modifications to the redox state of intracellular pyridine nucleotides in coronary smooth muscle and their impact on voltage-gated K + channels in metabolic vasodilation
- Subjects
BLOOD flow; HEART metabolism; SMOOTH muscle; REDUCTION potential; ALDO-keto reductases; ATRIAL flutter; CORONARY vasospasm
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-29745-z