Nitrosative stress drives heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a common, morbid, and mortal syndrome for which there are no evidence-based therapies. Here, we report that concomitant metabolic and hypertensive stress in mice elicited by a combination of high fat diet (HFD) and constitutive nitric oxide (NO) synthase inhibition by N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulates the numerous systemic and cardiovascular features of human HFpEF. One of the unfolded protein response (UPR) effectors, the spliced form of X-box binding protein 1 (Xbp1s), was reduced in the myocardium of both experimental and human HFpEF. Mechanistically, the decrease in Xbp1s resulted from increased inducible NO synthase (iNOS) activity and S-nitrosylation of endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective Xbp1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of Xbp1s, each ameliorated the HFpEF phenotype. We have unveiled iNOS-driven dysregulation of IRE1α-Xbp1s as a crucial mechanism of cardiomyocyte dysfunction in HFpEF.

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

“…However, our comprehensive functional, histological, and molecular phenotyping provides strong evidence that the aged C57BL/6 male mouse captures many of the major cardiac phenotypes that have been implicated as core pathophysiologic mediators of HFpEF (Borlaug, 2014). Importantly, the HFpEF phenotypes observed in aged C57BL/6 male mice occur in the absence of overt hypertension, which has been a common adjunct intervention used to generate HFpEF phenotypes in animal models (Eisenberg et al., 2016; Hulsmans et al., 2018; Schiattarella et al., 2019). Thus, we propose that the aged C57BL/6 male mouse not only represents a valuable and complementary model of HFpEF but is particularly well suited for studying the role of aging biology in HFpEF pathophysiology.…”

Cardiac nitric oxide synthase 1 worsens heart failure with preserved ejection fraction through S-nitrosylation of histone deacetylase 2

“…Although preliminary, our new findings that NO-mediated nitrosylation provokes HFpEF may explain why NO donors do not work in the clinical setting. Our study is not the only work to suggest NO as an inducer of HFpEF; indeed, a recent report also implied NOS/NO-mediated nitrosylation of protein in the development of HFpEF 35 . Thus, it is very likely that S-nitrosylation of key proteins may lead the scientific world to revisit NO as a potential therapeutic target of HFpEF.…”

Coronary microvascular dysfunction in heart failure with preserved ejection fraction – adding new pieces to the jigsaw puzzle

“…Hypertension, obesity, and coronary artery disease (CAD) are risk factors for HFpEF and the prevalence of this condition increases with age. There is experimental and clinical evidence that coronary endothelial inflammation and imbalance in nitric oxide (NO) production/utilisation, induced by co‐morbidities, are crucial in the pathophysiology of HFpEF . These abnormalities are in turn responsible for coronary microvascular dysfunction (CMD) and ischaemia, cardiomyocyte stiffening and hypertrophy, and/or myofibroblast activation, leading to left ventricular (LV) loss of lusitropic function .…”