Increased production of reactive oxygen species and failure of the antioxidant defense system are considered to play a central role in the pathogenesis of cardiovascular disease. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch controlling the expression of antioxidant and protective enzymes, and was proposed to participate in protection of vascular and cardiac function. This study was undertaken to analyze cardiac and vascular phenotype of mice lacking Nrf2. We found that Nrf2 knock out (Nrf2 KO) mice have a left ventricular (LV) diastolic dysfunction, characterized by prolonged E wave deceleration time, relaxation time and total diastolic time, increased E/A ratio and myocardial performance index, as assessed by echocardiography. LV dysfunction in Nrf2 KO mice was associated with cardiac hypertrophy, and a downregulation of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in the myocardium. Accordingly, cardiac relaxation was impaired, as demonstrated by decreased responses to β-adrenergic stimulation by isoproterenol ex vivo, and to the cardiac glycoside ouabain in vivo. Surprisingly, we found that vascular endothelial function and endothelial nitric oxide synthase (eNOS)-mediated vascular responses were fully preserved, blood pressure was decreased, and eNOS was upregulated in the aorta and the heart of Nrf2 KO mice. Taken together, these results show that LV dysfunction in Nrf2 KO mice is mainly associated with cardiac hypertrophy and downregulation of SERCA2a, and is independent from changes in coronary vascular function or systemic hemodynamics, which are preserved by a compensatory upregulation of eNOS. These data provide new insights into how Nrf2 expression/function impacts the cardiovascular system.

The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch that controls the expression of antioxidant and cytoprotective enzymes, including enzymes catalyzing glutathione de novo synthesis. In this study, we aimed to analyze whether Nrf2 deficiency influences antioxidative capacity, redox state, NO metabolites, and outcome of myocardial ischemia reperfusion (I/R) injury. In Nrf2 knockout (Nrf2 KO) mice, we found elevated eNOS expression and preserved NO metabolite concentrations in the aorta and heart as compared to wild types (WT). Unexpectedly, Nrf2 KO mice have a smaller infarct size following myocardial ischemia/reperfusion injury than WT mice and show fully preserved left ventricular systolic function. Inhibition of NO synthesis at onset of ischemia and during early reperfusion increased myocardial damage and systolic dysfunction in Nrf2 KO mice, but not in WT mice. Consistent with this, infarct size and diastolic function were unaffected in eNOS knockout (eNOS KO) mice after ischemia/reperfusion. Taken together, these data suggest that eNOS upregulation under conditions of decreased antioxidant capacity might play an important role in cardioprotection against I/R. Due to the redundancy in cytoprotective mechanisms, this fundamental antioxidant property of eNOS is not evident upon acute NOS inhibition in WT mice or in eNOS KO mice until Nrf2-related signaling is abrogated.

Significance: In this review, we discuss the role of nitric oxide (NO) as a key physiological mechanotransducer modulating both local and systemic heterocellular communication and contributing to the integrated (patho)physiology of the cardiovascular system. A deeper understanding of mechanotransduction-mediated local and systemic nodes controlling heterocellular communication between the endothelium, blood cells, and other cell types (e.g., cardiomyocytes) may suggest novel therapeutic strategies for endothelial dysfunction and cardiovascular disease.Recent Advances: Mechanical forces acting on mechanoreceptors on endothelial cells activate the endothelial NO synthase (eNOS) to produce NO. NO participates in (i) abluminal heterocellular communication, inducing vasorelaxation, and thereby regulating vascular tone and blood pressure; (ii) luminal heterocellular communication, inhibiting platelet aggregation, and controlling hemostasis; and (iii) systemic heterocellular communication, contributing to adaptive physiological processes in response to exercise and remote ischemic preconditioning. Interestingly, shear-induced eNOS-dependent activation of vascular heterocellular communication constitutes the molecular basis of all methods applied in the clinical routine for evaluation of endothelial function.Critical Issues and Future Directions: The integrated physiology of heterocellular communication is still not fully understood. Dedicated experimental models are needed to analyze messengers and mechanisms underpinning heterocellular communication in response to physical forces in the cardiovascular system (and elsewhere). Antioxid. Redox Signal. 26, 917–935.

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