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Published on: December 2, 2014
Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female
James R Sowers1, Javad Habibi2, Guanghong Jia2
1Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, MO 65212, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA; Research Service, Harry S Truman Memorial Veterans Hospital, 800 Hospital Dr, Columbia, MO 65201, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65212, USA; Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Objective:
Obesity is associated with myocardial fibrosis and impaired diastolic relaxation, abnormalities that are especially prevalent in women. Normal coronary vascular endothelial function is integral in mediating diastolic relaxation, and recent work suggests increased activation of the endothelial cell (EC) mineralocorticoid receptor (ECMR) is associated with impaired diastolic relaxation. As the endothelial Na+ channel (EnNaC) is a downstream target of the ECMR, we sought to determine whether EC-specific deletion of the critical alpha subunit, αEnNaC, would prevent diet induced-impairment of diastolic relaxation in female mice.
Methods And Materials:
Female αEnNaC KO mice and littermate controls were fed a Western diet (WD) high in fat (46%), fructose corn syrup (17.5%) and sucrose (17.5%) for 12-16 weeks. Measurements were conducted for in vivo cardiac function, in vitro cardiomyocyte stiffness and EnNaC activity in primary cultured ECs. Additional biochemical studies examined indicators of oxidative stress, including aspects of antioxidant Nrf2 signaling, in cardiac tissue.
Results:
Deletion of αEnNaC in female mice fed a WD significantly attenuated WD mediated impairment in diastolic relaxation. Improved cardiac relaxation was accompanied by decreased EnNaC-mediated Na+ currents in ECs and reduced myocardial oxidative stress. Further, deletion of αEnNaC prevented WD-mediated increases in isolated cardiomyocyte stiffness.
Conclusion:
Collectively, these findings support the notion that WD feeding in female mice promotes activation of EnNaC in the vasculature leading to increased cardiomyocyte stiffness and diastolic dysfunction.
