Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function

Abstract

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.

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

“…Nrf2 -null mice had lower systolic BP compared with WT mice (Fig. 1c), which was in line with findings reported in a previous publication [28]. Diabetes mildly increased BP (Fig.…”

“…In the present study, the systolic BP of Nrf2 -null mice was lower than that of WT mice. This result is in accordance with the finding by Erkens et al [28], which showed that elevated endothelial nitric-oxide synthase in the heart and aorta of Nrf2 -null mice was the reason for the low BP. Given that high BP accelerates diabetic nephropathy whereas the Nrf2 -null mice had lower BP along with severer diabetic renal injury, we may further conclude that NRF2 does play an important role in the prevention of diabetic nephropathy.…”

Transmural gradients of myocardial structure and mechanics: Implications for fiber stress and strain in pressure overload

“…Computational models of these differences in Ca 2+ dynamics within a finite element model of LV mechanics showed that this was not a factor in regulating end-systolic fiber strain, but that the effect of these gradients on fiber and cross-fiber strains in the LV is most apparent at early systole, rather than end-systole (Campbell et al, 2009). Even so, SERCA2a activity has been shown to affect contractility and relaxation in disease (Erkens et al, 2015), (Frank et al, 2003), and changes in regional distributions may play a role in mechanical function of the myocardium.…”

Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

“…Impaired diastolic function in these NRF2 knockouts was associated with mild cardiac hypertrophy but preserved systolic function. In addition, a significant decline in cardiac SERCA2a and total glutathione levels were found in the myocardium of these animals [83]. The results suggest that NRF2 is an essential regulator of cardiac diastolic function upon non-stressed physiological conditions and that its downregulation might cause severe maladaptive reactions.…”