Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF (19 to 21 months) rats to oxypurinol (1 mmol/L; n=4 and n=15, respectively) or placebo (n=3 and n=10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31±3% versus 67±3% in WKY, P <0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7±0.2 mm versus 7.0±0.4 mm in WKY, P <0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho–extracellular signal–regulated kinase were restored toward normal by oxypurinol ( P <0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca ²⁺ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.

Lista de Siglas/Abreviaturas 18 F-FDG – fluordesoxiglicose marcado com flúor-18 123 I-MIBG – meta-iodo-benzil-guanidina marcado com iodo-123 […] Diretriz da SBC sobre Diagnóstico e Tratamento de Pacientes com Cardiomiopatia da Doença de Chagas – 2023 Lista de Siglas/Abreviaturas 18 F-FDG – fluordesoxiglicose marcado com flúor-18 123 I-MIBG – meta-iodo-benzil-guanidina marcado com iodo-123 […] Diretriz da SBC sobre Diagnóstico e Tratamento de Pacientes com Cardiomiopatia da Doença de Chagas – 2023

Although protein S -nitrosylation is increasingly recognized as mediating nitric oxide (NO) signaling, roles for protein denitrosylation in physiology remain unknown. Here, we show that S -nitrosoglutathione reductase (GSNOR), an enzyme that governs levels of S -nitrosylation by promoting protein denitrosylation, regulates both peripheral vascular tone and β-adrenergic agonist-stimulated cardiac contractility, previously ascribed exclusively to NO/cGMP. GSNOR-deficient mice exhibited reduced peripheral vascular tone and depressed β-adrenergic inotropic responses that were associated with impaired β-agonist–induced denitrosylation of cardiac ryanodine receptor 2 (RyR2), resulting in calcium leak. These results indicate that systemic hemodynamic responses (vascular tone and cardiac contractility), both under basal conditions and after adrenergic activation, are regulated through concerted actions of NO synthase/GSNOR and that aberrant denitrosylation impairs cardiovascular function. Our findings support the notion that dynamic S -nitrosylation/denitrosylation reactions are essential in cardiovascular regulation.

Background— Neuronal nitric oxide synthase (NOS1) plays key cardiac physiological roles, regulating excitation-contraction coupling and exerting an antioxidant effect that maintains tissue NO-redox equilibrium. After myocardial infarction (MI), NOS1 translocates from the sarcoplasmic reticulum to the cell membrane, where it inhibits β-adrenergic contractility, an effect previously predicted to have adverse consequences. Counter to this idea, we tested the hypothesis that NOS1 has a protective effect after MI. Methods and Results— We studied mortality, cardiac remodeling, and upregulation of oxidative stress pathways after MI in NOS1-deficient (NOS1 ^−/− ) and wild-type C57BL6 (WT) mice. Compared with WT, NOS1 ^−/− mice had greater mortality (hazard ratio, 2.06; P =0.036), worse left ventricular (LV) fractional shortening (19.7±1.5% versus 27.2±1.5%, P <0.05), higher LV diastolic diameter (5.5±0.2 versus 4.9±0.1 mm, P <0.05), greater residual cellular width (14.9±0.5 versus 12.8±0.5 μm, P <0.01), and equivalent β-adrenergic hyporesponsiveness despite similar MI size. Superoxide production increased after MI in both NOS1 ^−/− and WT animals, although NO increased only in WT. NADPH oxidase ( P <0.05) activity increased transiently in both groups after MI, but NOS1 ^−/− mice had persistent basal and post-MI elevations in xanthine oxidoreductase activity. Conclusions— Together these findings support a protective role for intact NOS1 activity in the heart after MI, despite a potential contribution to LV dysfunction through β-adrenergic hyporesponsiveness. NOS1 deficiency contributes to an imbalance between oxidative stress and tissue NO signaling, providing a plausible mechanism for adverse consequences of NOS1 deficiency in states of myocardial injury.

Chagas heart disease: An overview of diagnosis, manifestations, treatment, and care