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

Author

Marc Matthew Dwenger, University of LouisvilleFollow

Date on Master's Thesis/Doctoral Dissertation

12-2021

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Nystoriak, Matthew

Committee Co-Chair (if applicable)

Bhatnagar, Aruni

Committee Member

Bhatnagar, Aruni

Committee Member

Jones, Steven

Committee Member

Hill, Bradford

Committee Member

Ceresa, Brian

Author's Keywords

Cardiovascular physiology; coronary blood flow; ion channel biology; cardiac metabolism

Abstract

The maintenance of myocardial oxygen supply during stress is essential for sustaining cardiac health. Enhancement of coronary blood flow upon increases in myocardial oxygen demand (i.e., hyperemia) relies on regulation of voltage-gated K⁺ (Kv) channels by their intracellular β subunits (i.e., Kvβ proteins). Considering that, Kvβ proteins are aldo-keto reductases (AKRs) and regulate Kv channel gating, we tested the hypothesis that elevation of myocardial oxygen demand modifies intracellular NAD(H) in arterial myocytes. Furthermore, we tested whether the resultant change in the redox state of the pyridine nucleotide pool directly regulates coronary Kv1 channel activity. High-resolution imaging mass spectrometry and live-cell fluorescent imaging revealed that augmented cardiac workload significantly increases the cytosolic NADH:NAD⁺ ratio in intramyocardial arterial myocytes. Intracellular pyridine nucleotide redox ratios reflecting elevated oxygen demand potentiated whole-cell I_Kv density and stimulated native Kv1 channel activity in a Kvβ2-dependent manner. Mutations in the Kvβ2 catalytic site prevented NADH-induced increases in Kv1 activity, abolished vasodilation in response to elevated L-lactate, and suppressed the relationship between myocardial blood flow and cardiac workload. These results indicate that the AKR activity and pyridine nucleotide sensitivity of Kvβ proteins regulate coronary vasoreactivity and blood flow to the heart during metabolic stress.

Recommended Citation

Dwenger, Marc Matthew, "Pyridine nucleotide redox potential in coronary smooth muscle couples myocardial blood flow to cardiac metabolism." (2021). Electronic Theses and Dissertations. Paper 3700.
https://doi.org/10.18297/etd/3700