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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.excitation-contraction coupling | nitroso-redox imbalance G uanosine 3′,5′-cyclic monophosphate (cGMP)-dependent and -independent signaling by nitric oxide (NO) has been described in many organ systems, including the cardiovascular (CV) system (1, 2). Accumulating evidence indicates that the principal non-cGMP signal is effected by the covalent attachment of NO to the thiol group of cysteine (Cys) residues (Snitrosylation) (3) and that this posttranslational modification may influence cardiac contractility (4) and peripheral vascular resistance (5) through effects on ion channels (6) and adrenergic receptors (7). Because deletion or inhibition of NO synthase (NOS) diminishes all forms of NO bioactivity and thus impairs both cGMP and S-nitrosylation signaling, it has been difficult to elucidate the exact roles of S-nitrosylation vs. cGMP in CV regulation.Investigation of the role of S-nitrosylation in cellular signaling has been aided by discovery of enzymes that metabolize Snitrosothiols (SNOs) without affecting NOS activity or levels of NO itself (mammalian enzymes that directly metabolize NO have not been identified) (8-10). In particular, S-nitrosoglutathione reductase (GSNOR), an enzyme involved in the removal of NO groups from Cys thiols in proteins (SNO-proteins) through metabolism of S-nitrosoglutathione (GSNO, which is in equilibrium with SNO-proteins), has been ascribed an indispensable role in regulating S-nitrosylation in the CV system (9). Although GSNOR does not affect baseline blood pressure, it mitigates hypotension induced by anesthetics and infectious agents (5) and plays an essential role in regulating both β-adrenergic receptor expression and responsiveness in the heart (7). These studies suggest that SNOs may exert physiological roles in the control of systemic hemodynamics and cardiac contractility.In the CV system, endothelial NOS (NOS3, eNOS) and neuronal NOS (NOS1, nNOS) subserve endothe...

Abstract-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. Key Words: xanthine oxidoreductase Ⅲ remodeling Ⅲ gene expression Ⅲ heart failure E merging data implicates oxidative stress (OS) in heart failure (HF) pathophysiology, contributing to cardiac remodeling, 1,2 mechanoenergetic uncoupling, 3,4 and depressed myofilament calcium sensitivity. 5,6 The major enzymatic sources of reactive oxygen species (ROS) in HF are xanthine oxidoreductase (XOR) 7 and nicotinamide adenine dinucleotide 2Ј-phosphate (NADPH) oxidase. 8 Several studies demonstrate XOR upregulation in animal models 4 -7,9,10 and in human dilated cardiomyopathy. 3,11 Functionally, XOR inhibition (XOI) acutely enhances myocardial mechanical efficiency in both animals and humans with HF. 3,4 However, whereas NADPH oxidase is implicated in ␣ 1 -adrenoreceptor stimulated hypertrophic signaling 12 and contributes to OS in reperfused hearts, playing a major role in post-myocardial infarction (MI) microvascular obstruction ("no-reflow" phenomenon) 13 and, like XOR, is increased in human HF, 8 the relative contribution of XOR and NADPH oxidase to HF pathophysiology requires further clarification.A recent series of studies has begun to examine the role of XOR in the cardiac remodeling process. 2,6,14 These data contribute to the growing argument implicating XOR as a key source of ROS in evolving HF. Whether inhibition of XOR can elicit reverse remodeling in established dilated cardiomyopathy remains unknown.Here we tested the hypothesis that cardiac XOR adversely affects cardiac remodeling in established cardiomyopathy in spontaneously hypertensive/HF (SHHF) rats. We show that chronic XOI reverses maladaptive cardiac remodeling through effects on cardiac structure, function, and fetal gene activation in SHHF rats, and that this process occurs independently of NADPH oxidase.

CONTEXT Research activity is not a mandatory component of medical education in many developing countries, including Brazil, although such experiences can have a positive impact on the quality of medical education. The interest and involvement of medical students in research and the barriers they face in accessing research training in developing countries have not been adequately addressed.OBJECTIVES We sought to assess the availability of scientific training programmes in Brazilian medical schools, the degree of involvement of medical students in these programmes, the main barriers to student involvement in research and possible reasons for the lack of scientific training programmes.METHODS This study examined 13 medical programmes conducted in six Brazilian states. A total of 1004 medical students were interviewed. We evaluated the availability of scientific training in the institutions attended by these students, the participation of the students in such activities and students' reasons for not joining such programmes based on student answers to our questionnaire.RESULTS Although only 7% of the medical students expressed no interest in research, only 60% of them were involved in research training. Students regarded a lack of institutional incentive as the most significant barrier to their participation in research activities. Other significant barriers included defective infrastructure and insufficient time available for professors to mentor undergraduate students. According to the feedback from the students, eight of the 13 schools investigated featured structured programmes for scientific training. However, a mean of only 47% of students participated in scientific training programmes on their campuses and 13% of students were compelled to pursue such activities off-campus.CONCLUSIONS Although scientific training during medical education in Brazil is still less frequent than expected, most of the students were interested in research activities. The barriers to undergraduate scientific training described in this paper may help the Brazilian government improve research training in medical schools. These issues might also be explored in other developing countries.

Background-Neuronal nitric oxide synthase (NOS1) plays key cardiac physiological roles, regulating excitationcontraction 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 ␤-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 Ϫ/Ϫ and WT animals, although NO increased only in WT. NADPH oxidase (PϽ0.05) activity increased transiently in both groups after MI, but NOS1 Ϫ/Ϫ 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 ␤-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.