Key result
BH4 depletion increases LVEDP by ~8 mmHg with preserved LVEF, an effect reversed by Tempol.
Why the study?
HFpEF lacks effective disease-specific therapies, and increasing evidence implicates impaired nitric oxide bioavailability and oxidative stress in its pathogenesis. Whether pharmacologic BH4 depletion induces constitutive nitric oxide synthase uncoupling sufficient to produce diastolic dysfunction consistent with HFpEF was unknown.
Does pharmacologic BH₄ depletion via DAHP induce constitutive NOS uncoupling and diastolic dysfunction consistent with HFpEF in male C57BL/6J mice, and does Tempol reverse this phenotype?
Does pharmacologic BH₄ depletion via DAHP induce constitutive NOS uncoupling and diastolic dysfunction consistent with HFpEF in male C57BL/6J mice, and does Tempol reverse this phenotype?
Pharmacologic BH₄ depletion in mice induces HFpEF-like diastolic dysfunction via constitutive NOS uncoupling and oxidative stress, establishing a mechanistically defined preclinical model of HFpEF.
Caution against clinical translation of BH4 modulation; extends preclinical HFpEF models via NOS uncoupling but remains hypothesis-generating.
Background Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases and lacks effective disease-specific therapies. HFpEF is strongly associated with metabolic comorbidities and endothelial dysfunction, and increasing evidence implicates impaired nitric oxide (NO) bioavailability and oxidative stress in its pathogenesis. Constitutive nitric oxide synthases (NOS) require tetrahydrobiopterin (BH₄) for appropriate enzymatic coupling and NO generation. BH₄ deficiency promotes NOS uncoupling, resulting in superoxide production, peroxynitrite formation and redox imbalance, thereby shifting the myocardial and vascular environment towards oxidative injury. Purpose To determine whether pharmacologic BH₄ depletion induces constitutive NOS uncoupling sufficient to produce diastolic dysfunction consistent with HFpEF, and to assess the contribution of oxidative stress to this phenotype. Methods Male C57BL/6J mice received the GTP cyclohydrolase I inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) in drinking water to induce systemic BH₄ depletion. Left ventricular end-diastolic pressure (LVEDP) and right ventricular systolic pressure (RVSP) were measured by invasive catheterisation. LV systolic and diastolic function was assessed by echocardiography. Myocardial nitrosative stress was quantified by nitrotyrosine immunoblotting. To evaluate redox causality, a subset received the superoxide dismutase mimetic Tempol. Additional cohorts were exposed to high-fat diet (HFD) or chronic hypoxia to model metabolic and cardiopulmonary stress. Results DAHP treatment increased LVEDP from 5.2 ± 0.6 to 12.8 ± 1.1 mmHg (p<0.001) whilst preserving left ventricular ejection fraction (62 ± 3% vs 60 ± 2%, NS). Myocardial nitrotyrosine levels increased 2.4-fold (p<0.01), confirming nitrosative stress. RVSP rose modestly (+5 mmHg, p<0.05), attributable to elevated left-sided filling pressures. Tempol significantly reduced LVEDP (12.8 ± 1.1 to 7.1 ± 0.9 mmHg, p<0.01), implicating oxidative stress as a mechanistic contributor to diastolic dysfunction. Chronic hypoxia had no additive effects, whereas HFD further increased LVEDP (+35% vs DAHP alone, p<0.01) and worsened diastolic dysfunction. Conclusions Pharmacologic BH₄ depletion induces HFpEF-like physiology through constitutive NOS uncoupling and oxidative stress dependent mechanisms. These findings identify redox imbalance as a functional driver of diastolic dysfunction and establish a mechanistically defined, single-hit model that recapitulates key haemodynamic features of human HFpEF. This platform provides a rational basis for evaluating redox-targeted and NOS coupling therapeutic strategies in HFpEF.
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Gupta et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF) murine model. 2,4-diamino-6-hydroxypyrimidine (DAHP) in drinking water (with a subset receiving Tempol) vs. Untreated control mice was evaluated on Left ventricular end-diastolic pressure (LVEDP) (p=<0.001).
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