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Nitrosative stress drives heart failure with preserved ejection fraction
Gabriele G Schiattarella1,2, Francisco Altamirano1, Dan Tong1
1Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|April 12, 2019
Summary
Heart failure with preserved ejection fraction (HFpEF) lacks effective treatments. Researchers found that inhibiting nitric oxide synthase in mice mimicked HFpEF, revealing a pathway involving X-box-binding protein 1 (XBP1s) crucial for heart function.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pathophysiology
Background:
- Heart failure with preserved ejection fraction (HFpEF) presents a significant clinical challenge with high morbidity and mortality.
- Current therapeutic strategies for HFpEF are limited, lacking evidence-based treatments.
Purpose of the Study:
- To investigate the molecular mechanisms underlying HFpEF.
- To identify potential therapeutic targets for HFpEF.
Main Methods:
- A mouse model was developed using a high-fat diet and N-nitro-L-arginine methyl ester (L-NAME) to induce metabolic and hypertensive stress, mimicking HFpEF.
- Investigated the expression and function of the unfolded protein response effector X-box-binding protein 1 (XBP1s) in the myocardium.
- Examined the role of inducible nitric oxide synthase (iNOS) and the IRE1α-XBP1 pathway in HFpEF pathogenesis.
Main Results:
- The mouse model successfully recapitulated key systemic and cardiovascular features of human HFpEF.
- Reduced myocardial XBP1s expression was observed in both the HFpEF mouse model and human patients.
- Increased iNOS activity and subsequent S-nitrosylation of IRE1α led to defective XBP1 splicing and contributed to the HFpEF phenotype.
- Suppression of iNOS or enhancement of XBP1s ameliorated the HFpEF phenotype in the mouse model.
Conclusions:
- Dysregulation of the IRE1α-XBP1 pathway, driven by iNOS, is a critical mechanism contributing to cardiomyocyte dysfunction in HFpEF.
- Targeting the iNOS-IRE1α-XBP1 pathway may offer a novel therapeutic approach for HFpEF.
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