Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the failing heart, NADPH oxidase and uncoupled NO synthase utilize cytosolic NADPH to form superoxide. NADPH is supplied principally by the pentose phosphate pathway, whose rate-limiting enzyme is glucose 6-phosphate dehydrogenase (G6PD). Therefore, we hypothesized that cardiac G6PD activation drives part of the excessive superoxide production implicated in the pathogenesis of heart failure. Pacing-induced heart failure was performed in eight chronically instrumented dogs. Seven normal dogs served as control. End-stage failure occurred after 28 +/- 1 days of pacing, when left ventricular end-diastolic pressure reached 25 mm Hg. In left ventricular tissue homogenates, spontaneous superoxide generation measured by lucigenin (5 microM) chemiluminescence was markedly increased in heart failure (1338 +/- 419 vs. 419 +/- 102 AU/mg protein, P < 0.05), as were NADPH levels (15.4 +/- 1.5 vs. 7.5 +/- 1.5 micromol/gww, P < 0.05). Superoxide production was further stimulated by the addition of NADPH. The NADPH oxidase inhibitor gp91(ds-tat) (50 microM) and the NO synthase inhibitor L-NAME (1 mM) both significantly lowered superoxide generation in failing heart homogenates by 80% and 76%, respectively. G6PD was upregulated and its activity higher in heart failure compared to control (0.61 +/- 0.10 vs. 0.24 +/- 0.03 nmol/min/mg protein, P < 0.05), while superoxide production decreased to normal levels in the presence of the G6PD inhibitor 6-aminonicotinamide. We conclude that the activation of myocardial G6PD is a novel mechanism that enhances NADPH availability and fuels superoxide-generating enzymes in heart failure.
 ...
PMID:Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart. 1682 94

A common gene variant of human extracellular superoxide dismutase (ecSOD), in approximately 5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSOD(R213G)) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSOD(R213G), or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 +/- 4% relaxation, means +/- SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 +/- 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 +/- 0.2 to 0.9 +/- 0.2 relative light units per second per millimeter squared (RLU x s(-1) x mm(-2))] and peroxynitrite (from 2.4 +/- 0.2 to 0.9 +/- 0.1 RLU x s(-1) x mm(-2)) in the aorta from rats with heart failure. Gene transfer of ecSOD(R213G) produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSOD(R213G) in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSOD(R213G) in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSOD(R213G).
 ...
PMID:Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure. 1684 Jul 38

Pressure overload associated with hypertension is an important pathological factor leading to heart remodeling and ultimately heart failure partially due to cardiomyocyte apoptosis. Here we show that endogenous NO signaling plays a critical role in mechanical stretch-induced cardiomyocyte apoptosis. Mechanical stretch induced elevated expression of both eNOS and inducible NO synthase (iNOS) and increased synthesis of NO. A sustained increase in iNOS expression was also found in hearts of hypertensive rats in vivo. Blockade of NO signaling by inhibitors of NOS (L-NAME and AMT) or downstream guanylyl cyclase (ODQ) strongly inhibited stretch-induced apoptosis, mitochondria depolarization, and cytochrome c release, suggesting that NO is required in stretch-induced cardiomyocyte apoptosis. The expression of iNOS, but not eNOS, was blocked by L-NAME and ODQ, indicating that the iNOS induction is NO dependent. The initial elevation of NO is likely due to Ca(2+)-dependent activation of eNOS because elimination of intracellular calcium by EGTA-AM inhibited both iNOS induction and NO elevation. Other calcium signaling inhibitors (nifedipine, ryanodine, thapsigargin, and ionic gadolinium) also attenuated the initial NO elevation. These data indicate that mechanical signals initiate Ca(2+)-dependent NO synthesis, which is further amplified by activation of NO-induced iNOS expression, to regulate cardiomyocyte apoptosis.
 ...
PMID:Nitric oxide signaling in stretch-induced apoptosis of neonatal rat cardiomyocytes. 1687 24

Our previous study demonstrated a contribution of the paraventricular nucleus (PVN) of the hypothalamus in the processing of the carotid body (CB) chemoreflex. Nitric oxide (NO) (within the PVN), known to modulate autonomic function, is altered in rats with heart failure (HF). Therefore, the goal of the present study was to examine the influence of endogenous and exogenous NO within the PVN on the sympathoexcitatory component of the peripheral chemoreflex in normal and HF states. We measured mean arterial blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) in sham-operated and HF rats (6-8 wk after coronary artery ligation) after incremental doses of potassium cyanide (25-100 mug/kg iv). There was potentiation of the reflex responses in HF compared with sham-operated rats. Bilateral microinjection of an inhibitor of NO synthase, N(G)-monomethyl-l-arginine (50 pmol), into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation in sham-operated rats but had no effect in HF rats. Conversely, bilateral microinjection of a NO donor, sodium nitroprusside (50 nmol), into the PVN attenuated the RSNA response of the peripheral chemoreflex in sham-operated rats but to a smaller extent in HF rats. These data indicate that 1) NO within the PVN plays an important role in the processing of the CB chemoreflex and 2) there is an impairment of the NO function within the PVN of HF rats, which contributes to an augmented peripheral chemoreflex and subsequent elevation of sympathetic activity in HF.
 ...
PMID:Altered nitric oxide mechanism within the paraventricular nucleus contributes to the augmented carotid body chemoreflex in heart failure. 1689 8

Dietary copper (Cu) deficiency leads to cardiac morphological and functional defects suggestive of heart failure. However, simultaneous cytoprotective events also appear to occur. The molecular mechanisms responsible for this complex alteration of cardiac function by Cu deficiency have not been elucidated. Because prior work has implicated altered nitric oxide (NO) metabolism in this altered function, we have examined this pathway in further detail. Male Sprague-Dawley rats were fed diets that were either Cu adequate (6 mg Cu/kg diet) or Cu deficient (<0.5 mg Cu/kg diet) for 5 weeks. Endothelial NO synthase (NOS) and inducible NOS (iNOS) protein expressions, as measured by Western blot analysis, were 58% and 40% higher, respectively, in Cu-deficient than in Cu-adequate rat hearts. Cardiac NOS activity, as measured by conversion of (3)H-arginine to (3)H-citrulline, was 130% higher in Cu-deficient than in Cu-adequate rats. NFkappaB is a known transcription factor for iNOS. Activation of NFkappaB, determined by an ELISA for the p65 subunit, was found to be 33% higher in Cu-deficient than in Cu-adequate rats. Coupled with prior evidence of elevated cardiac nitrate/nitrite production in Cu-deficient rats, these data suggest multiple pathways for enhanced NO production that may contribute to altered cardiac function under dietary Cu deficiency.
 ...
PMID:Cardiac nitric oxide synthases are elevated in dietary copper deficiency. 1699 40

Reduced activity and expression of endothelial NO synthase (eNOS) is observed in cardiomyocytes from pressure-overloaded hearts with heart failure. The present study was aimed to investigate whether reduced eNOS-derived NO production contributes to the hypertrophic growth and phenotype of these cardiomyocytes. Cultured ventricular cardiomyocytes from adult rats were exposed to Nomega-nitro-l-arginine (l-NNA) to inhibit global NO formation, and cultured cardiomyocytes derived from eNOS-deficient mice were used as a model of genetic knockout of eNOS. Cell growth, formation of oxygen-derived radicals (reactive oxygen species [ROS]), activation of p38 mitogen-activated protein (MAP) kinase phosphorylation, and cytokine expression in cardiomyocytes were investigated. l-NNA caused a concentration-dependent acceleration of the rate of protein synthesis and an increase in cell size. This effect was sensitive to p38 MAP kinase inhibition or antioxidants. l-NNA induced a rapid increase in ROS formation, subsequent activation of p38 MAP kinase, and p38 MAP kinase-dependent increases in the expression of transforming growth factor-beta and tumor necrosis factor-alpha. Similar changes (increased ROS formation, p38 MAP kinase phosphorylation, and cytokine induction) were also observed in cardiomyocytes derived from eNOS+/+ mice when exposed to l-NNA. Cardiomyocytes from eNOS-/- mice displayed higher p38 MAP kinase phosphorylation and cytokine expression under basal conditions, but neither these 2 parameters nor ROS formation were increased in the presence of l-NNA. In conclusion, our data support the hypothesis that reduced eNOS activity in cardiomyocytes contributes to the onset of myocardial hypertrophy and increased cytokine expression, which are involved in the transition to heart failure.
 ...
PMID:Lack of endothelial nitric oxide synthase-derived nitric oxide formation favors hypertrophy in adult ventricular cardiomyocytes. 1707 27

Nitric oxide synthase (NOS) expression in human intracardiac ganglia was studied using two techniques--histochemical demonstration of NADPH-diaphorase and immunohistochemical staining for NOS. To detect the influence of coronary heart disease on NOS expression, hearts were studied in patients that died from heart failure (n = 8) and in persons that died in accidents (n = 3, control). It was found that human intracardiac neurons normally expressed mainly NOS1, and the proportion of these cells amounted to about 40%. A portion of neurons with low and moderate density of staining for NADPH-diaphorase was increased in ischemic myocardium, probably, due NOS2 induction.
 ...
PMID:[Nitric oxide synthase in human intracardiac ganglia in the normal and ischemic myocardium]. 1711 56

Nitric oxide (nitrogen monoxide) (NO) plays an important role in a wide range of physiologic processes. A major mediator of endothelial function, NO regulates vasodilatory and antithrombotic actions in the vasculature and plays a role in reproductive functions, bronchodilation, bone formation, memory, insulin sensitivity, and gastrointestinal relaxation. NO is formed from NO synthase. Impaired NO bioactivity is strongly associated with endothelial dysfunction and cardiovascular disease, but is also implicated in a broad range of other disorders, including pulmonary hypertension, insulin resistance, erectile dysfunction, and preeclampsia. Numerous therapies designed to target NO are being investigated and developed, including NO donors and stimulants. The recent African-American Heart Failure Trial (A-HeFT) showed that the NO donor isosorbide dinitrate, combined with the vasodilator hydralazine, significantly reduced morbidity and mortality in black patients with moderate-to-severe heart failure. Antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation beta-blockers, are NO stimulants that have demonstrated significant improvement of endothelial function and NO bioactivity. Other cardiovascular therapies that may improve NO bioactivity include statins, l-arginine, and nonpharmacologic approaches such as exercise and dietary changes.
 ...
PMID:Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. 1717 Jun 2

Carvedilol's adrenergic antagonism does not fully explain its therapeutic actions. We therefore tested the hypothesis that its action is associated with an increase in NO synthesis. Wistar rats (male, 9 weeks, n = 10) anesthetized with sodium pentobarbital were used. Arterial NO concentration ([NO]), determined by chemiluminescence, and mean arterial pressure (MAP) were monitored throughout the experiment. In protocol 1), the effects of carvedilol (1 mg/kg, iv) were studied over a eriod of 90 min. In protocol 2), carvedilol was p administered, followed by the NO synthase (NOS) inhibitor L-NAME (5 mg/kg, iv) and by a second carvedilol administration. In protocol 1), carvedilol induced a significant fall in MAP (from 125,0 +/- 4,5 mmHg to 78.2 +/- 2.6 mmHg; p <0.001), reaching a minimum at t = 11.7 +/- 2.1 min and recovering 60 min afterwards (105.7 +/- 5.9 mmHg). Plasma [NO] varied in response to carvedilol in inverse proportion to MAP: baseline, 19.8 +/- 0.9 microM; t = 11.7 +/- 2.1 min, 32,3 +/- 2,3 microM; t = 60 min, 17.3 +/- 1.9 microM. In protocol 2), L-NAME administration blocked the effects of carvedilol (L-NAME: MAP, 129.9 +/- 5.0 mmHg; [NO], 13,1 +/- 2,3 microM. Post-L-NAME carvedilol administration resulted in MAP of 108.3 +/- 8.0 mmHg, NS, and [NO], 21.3 +/- 1.3 microM, NS. These results suggest that carvedilol increases plasma [NO], which is associated with a fall in MAP. Furthermore, carvedilol's hemodynamic action was blocked by NOS inhibition, suggesting that it depends on endogenous NO production, thus possibly explaining carvedilol's effects in hypertension and in cardiac failure.
 ...
PMID:Carvedilol's actions are largely mediated by endogenous nitric oxide. 1719 Feb 40

In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). Heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk, and cardiac recovery (CR) was allowed by the termination of cardiac pacing for 3-4 wk after the development of CHF, in which left ventricular contractile function was restored by 80-90%. The endothelium-dependent CBF response to bradykinin and acetylcholine was depressed in CHF and fully restored in CR. Myocardial NOx (nitrate/nitrite), endothelial NO synthase (eNOS) mRNA expression, total protein, and phosphorylated eNOS decreased significantly in failing hearts. However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser(239) in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.
 ...
PMID:Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling. 1732 19


<< Previous 1 2 3 4 5 6 7 8 9 10