Deficiency of the transcription factor, Nrf2, impairs vasomotor responses and limits exercise training‐induced adaptations of coronary arterioles
Authors: Medarev Steven Lee , Park Hyerim , Restrepo Alexis , Dewell Isabella , Wahl John , Wahl Jake , Vega‐Figueroa Leilanie , McKinley‐Caspanello Carly , Moraj Josh , Peterson William , Reid‐Foley Emily , Ballehr Kelsey , Schwartz Kaley , Sadowsky Dylan , Bedwell Kristin , Delp Michael , Geurts Aron , Delp Judy 
Published: June 2021

Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a transcription factor that is crucial in maintaining cellular redox homeostasis. Vasomotor responses of the coronary resistance vasculature and regulation of coronary blood flow are closely linked to myocardial metabolism and redox status of the myocardium. We hypothesized that deletion of Nrf2 would alter vascular responses of coronary arterioles and limit exercise training‐induced adaptations of vasomotor function. We exercise trained wild type (WT) Sprague‐Dawley rats, and their littermates that were lacking the Nrf2 gene (Nrf2KO). Rats were either exercise trained (EX) on a motor‐driven treadmill 5 days/wk or remained sedentary (SED) in their cages for 10–12 weeks. A mixed moderate aerobic and high‐intensity interval training protocol was utilized. At the end of the training period, coronary arterioles were isolated for assessment of vasomotor responses to potassium chloride (KCl) and endothelin, as both are considered potential endogenous regulators of coronary vascular resistance. We also evaluated responsiveness of coronary arterioles to increasing intraluminal pressure (the myogenic response). Contractile responses of coronary arterioles to KCl and endothelin were reduced in arterioles from sedentary Nrf2KO rats as compared to arterioles from sedentary WT rats. Low concentrations of KCl induced vasodilation in coronary arterioles from exercise trained WT rats but not in arterioles from sedentary WT rats. Constriction to high concentrations of KCl was reduced in arterioles from exercise trained WT rats as compared to those from sedentary WT (WT EX vs WT SED; P<0.01); however, these adaptations to exercise training were absent in arterioles from Nrf2KO rats (KO EX vs KO SED; P=0.94). Exercise training altered vasoconstrictor responses to endothelin in coronary arterioles from both WT and Nrf2KO rats; however, the effects of exercise training were directionally opposite in arterioles from WT and Nrf2KO rats. In arterioles from WT rats, exercise training reduced vasoconstrictor responses to endothelin, whereas in arterioles from Nrf2KO rats, vasoconstrictor responses to endothelin were increased by exercise training. Myogenic responsiveness was decreased in coronary arterioles from Nrf2KO rats as compared to arterioles from WT rats, but exercise training did not alter myogenic responsiveness in arterioles from either WT or Nrf2KO rats. These data suggest that the contractile responsiveness of coronary arterioles is decreased in the absence of Nrf2. The absence of Nrf2 also limits adaptation of coronary arterioles in response to exercise training. These changes in arteriolar function may be linked to alterations of redox homeostasis and metabolite production in cardiac muscle that is deficient in Nrf2.Support or Funding InformationNIH R15AG055029This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.