Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cigarette smoking is associated with impaired endothelium-dependent vasodilation and reduced nitric oxide (NO) in the exhaled air of smokers. To explore the mechanism for the impairment of NO-mediated vasodilation, we studied the effect of cigarette smoke extract (CSE) on NO synthase (eNOS) activity and content in pulmonary artery endothelial cells (PAEC). Incubation of PAEC with CSE resulted in a time- and dose-dependent decrease in eNOS activity. The inhibitory effect of CSE on eNOS activity was not reversible. Both gas-phase and particulate-phase extracts of CSE contributed to the inhibition of eNOS activity. The protein kinase c (PKC) inhibitors staurosporine and chelerythrine did not affect the CSE-induced inhibition of eNOS activity. Catalase, superoxide dismutase (SOD), vitamin C, vitamin E, glutathione, and dithiothreitol (DTT) also did not prevent the CSE-induced inhibition of eNOS activity, and incubation of PAEC with 3 mM nicotine did not change the activity of eNOS. Treatment of PAEC with CSE also caused a nonreversible, time-dependent decrease in eNOS protein content detected by Western blot analysis, and in eNOS messenger RNA (mRNA) detected by Northern blot analysis. Treatment of PAEC with CSE had no effect on cell protein or glutathione contents or on lactate dehydrogenase (LDH) release. These results indicate that exposure to CSE causes an irreversible inhibition of eNOS activity in PAEC, and suggest that the decreased activity is secondary to reduced eNOS protein mass and mRNA. The decrease in eNOS activity may contribute to the high risk of pulmonary and cardiovascular disease in cigarette smokers.
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PMID:Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. 980 47

Nitric oxide (NO) produced in endothelial cells has been implicated in the regulation of blood pressure, regional blood flow, inhibition of platelet aggregation, and endothelial and vascular smooth muscle cell proliferation. In a variety of cardiovascular disease states, such as atherosclerosis, arterial hypertension, and restenosis, expression of endothelial NO synthase (NOS-III) and endothelial NO production appear to be altered. Thus, NOS-III is an attractive target for cardiovascular gene therapy for which adenoviral vectors are one of the most effective vector systems. Therefore, a recombinant adenoviral vector expressing NOS-III (adenovirus type 5 [Ad5] cytomegalovirus [CMV] NOSIII) was constructed and biochemically and pharmacologically characterized both in vitro and in intact cells. Ad5CMVNOSIII-derived recombinant NOS-III was successfully expressed, as shown by immunoprecipitation and immunocytochemistry, and biologically active, as shown by functional assays in human primary umbilical vein and EA.hy926 endothelial cells, as well as 293 human embryonic kidney and Chinese hamster ovary cells. The Km values for NADPH and L-arginine and the Ka for tetrahydrobiopterin as well as the enzyme's dependency on other cofactors were similar to recombinant reference enzyme and literature values. NOS-III expression levels correlated linearly with the multiplicity of infection with Ad5CMVNOSIII and lasted for at least 8 days. NOS-III transfection inhibited endothelial cell proliferation. In conclusion, adenovirus-mediated gene transfer of Ad5CMVNOSIII to vascular and nonvascular cells resulted in the dose-dependent expression of intact, physiologically regulated, and functionally active NOS-III.
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PMID:Biochemical and functional characterization of nitric oxide synthase III gene transfer using a replication-deficient adenoviral vector. 1048 73

Alzheimer's disease (AD) has heterogeneous pathology, in part due to the large subset of cases (AD+CVD) with superimposed vascular lesions that are sufficient in number and distribution to accelerate the clinical course of dementia. Brains with AD+CVD have lower densities of neurofibrillary tangles and A beta-amyloid diffuse plaques, and increased numbers of cerebral vessels exhibiting p53-associated apoptosis relative to brains with uncomplicated AD. AD and AD+CVD both exhibit altered expression of the nitric oxide synthase 3 (NOS-III) gene; however, in AD+CVD, reduced NOS-III expression in cerebral vessels is associated with an increased frequency of vascular lesions, vascular smooth muscle cell apoptosis, and A beta-amyloid plaques. In contrast, experimental and spontaneous focal acute and subacute cerebral infarcts are associated with increased NOS-III expression in perifocal neurons, glial cells, cerebrovascular smooth muscle and endothelial cells, and diffuse A beta-amyloid plaque formation. This suggests that ischemic injury and oxidative stress can precipitate NOS-III-mediated cell loss and neurodegeneration. A role for aging-associated impaired mitochondrial function as a contributing factor in AD and CVD is suggested by the reduced levels of mitochondrial protein observed in AD and AD+CVD cortical neurons and vascular smooth muscle and endothelial cells. The aggregate findings suggest that cell loss and neurodegeneration may be mediated by somewhat distinct but overlapping mechanisms in AD and AD+CVD.
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PMID:Aberrant expression of nitric oxide synthase III in Alzheimer's disease: relevance to cerebral vasculopathy and neurodegeneration. 1086 16

Vascular endothelial dysfunction is now recognized as a common phenomenon in an array of cardiovascular disorders. Production of nitric oxide via the endothelial isoform of nitric oxide synthase [eNOS (previously termed NOS3 or ecNOS)] is vital for a healthy endothelium; several polymorphic variations of the gene encoding eNOS (NOS3) are now known and have been investigated with respect to disease risk. Surprisingly, only approximately half of these studies have demonstrated significant associations between NOS3 polymorphisms and cardiovascular disease, and many reports are contradictory. Central issues include adequate statistical power, appropriateness of control cohorts, multigene interactions and plausible biological consequences. So far, the inconsistencies are not unique to the NOS3 polymorphisms, but probably represent the broad challenges in defining genetic aspects of complex disease processes.
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PMID:Therapeutic implications of human endothelial nitric oxide synthase gene polymorphism. 1143 Oct 31

1. Red wine intake is associated with a low risk of cardiovascular disease. This effect has been partly attributed to the action of polyphenolic compounds, which decrease the oxidation of plasma low density lipoproteins. Moreover, nitric oxide ((*)NO) is a vasodilator and polyphenolic compounds induce endothelium-dependent vasorelaxation in vitro. 2. Here we studied whether a diet rich in dealcoholated red wine (DRW) increases acetylcholine-induced vasorelaxation and whether ingestion of DRW-, quercetin- or catechin-rich diets modifies the (*)NO-cyclic guanosine-3',5'-monophosphate (cyclic GMP) pathway and superoxide anion (O2(.-)) release in aorta in a resting state in rats fed semi-purified diets containing either 35% (v w(-1)) DRW, 0.3% (w w(-1)) quercetin or 0.3% (w w(-1)) catechin for 10 days. 3. (*)NO-mediated vasorelaxation induced by acetylcholine was greater in rats fed the DRW-rich diet than in those that received the control diet. 4. Expression of endothelial (*)NO synthase (eNOS) was similar in the four dietary groups. The aortic rings of rats fed either the DRW-, quercetin-, or catechin-rich diets showed higher NOS activity, (*)NO production and cyclic GMP content than those of rats fed the control diet. No changes were observed in O2(.-) production. 5. In summary, diets rich in either DRW, quercetin or catechin induced endothelium-dependent vasorelaxation in rat aorta in a resting state through the enhancement of (*)NO production, without modifying O2(.-) generation, thus the bioavailability of (*)NO was increased. The increase in the (*)NO-cyclic GMP pathway explains the beneficial effect of flavonoids at vascular level.
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PMID:A flavonoid-rich diet increases nitric oxide production in rat aorta. 1186 18

Angiotensin-converting enzyme inhibitors (ACEi) reduce cardiovascular morbidity and mortality by improving coronary perfusion, reducing ventricular hypertrophy and remodeling, and preventing progression of coronary atherosclerosis. However, the cellular mechanisms underlying the beneficial effects of ACEi are not fully understood. We studied the in vivo effects of ACE inhibition with perindopril on cellular expression of ACE, AT(1) receptors and 2 nitric oxide synthase (NOS) isoforms, endothelial (eNOS) and inducible NOS (iNOS), in human blood vessels using quantitative in vitro autoradiography and immunocytochemistry. Seven patients with ischemic heart disease were treated with perindopril (4 mg/d) for up to 5 weeks before elective coronary bypass surgery, whereas controls did not receive the ACEi (n=7). Perindopril decreased plasma ACE by 70% and the plasma angiotensin II to angiotensin I ratio by 57% and reduced vascular ACE to approximately 65% of control levels in both endothelium and adventitia. By contrast, AT(1) receptor binding in vascular smooth muscle cells was increased by 80% in patients treated with perindopril as confirmed by immunocytochemistry. eNOS was expressed primarily in endothelial cells, whereas little iNOS expression occurred in vascular smooth muscle cells of untreated patients. Both eNOS and iNOS expression seemed to increase during perindopril treatment. These results suggest that suppression of angiotensin II formation in the vascular wall and increased expression of eNOS and iNOS during ACE inhibition may be beneficial in reversing endothelial dysfunction in patients with cardiovascular disease. Because vascular AT(1) receptor expression is increased during chronic ACE inhibition, more clinical studies are required to determine whether it is necessary to combine ACE inhibitors and AT(1) receptor antagonists in clinical management of heart failure, coronary heart disease, and hypertension
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PMID:Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease. 1236 66

Gene therapy refers to the transfer of specific genes to the host tissue to intervene in a disease process, with resultant alleviation of the symptoms of a particular disease. Cardiovascular gene transfer is not only a powerful technique for studying the function of specific genes in cardiovascular biology and pathobiology, but also a novel and promising strategy for treating cardiovascular diseases. Since the mid-1990s, nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO) from L-arginine, has received considerable attention as a potential candidate for cardiovascular gene therapy, because NO exerts critical and diverse functions in the cardiovascular system, and abnormalities in NO biology are apparent in a number of cardiovascular disease processes including cerebral vasospasm, atherosclerosis, postangioplasty restenosis, transplant vasculopathy, hypertension, diabetes mellitus, impotence and delayed wound healing. There are three NOS isoforms, i.e., endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). All three NOS isoforms have been used in cardiovascular gene transfer studies with encouraging results. This review will discuss the rationale of NOS gene therapy in different cardiovascular disease settings and summarize the results of experimental NOS gene therapy from various animal models of cardiovascular disease to date.
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PMID:Nitric oxide synthase gene therapy for cardiovascular disease. 1223 10

Cardiovascular diseases remain the leading cause of death in the United States. Two factors associated with a decreased risk of developing cardiovascular disease are elevated HDL levels and sex - specifically, a decreased risk is found in premenopausal women. HDL and estrogen stimulate eNOS and the production of nitric oxide, which has numerous protective effects in the vascular system including vasodilation, antiadhesion, and anti-inflammatory effects. We tested the hypothesis that HDL binds to its receptor, scavenger receptor class B type I (SR-BI), and delivers estrogen to eNOS, thereby stimulating the enzyme. HDL isolated from women stimulated eNOS, whereas HDL isolated from men had minimal activity. Studies with ovariectomized and ovariectomized/estrogen replacement mouse models demonstrated that HDL-associated estradiol stimulation of eNOS is SR-BI dependent. Furthermore, female HDL, but not male HDL, promoted the relaxation of muscle strips isolated from C57BL/6 mice but not SR-BI null mice. Finally, HDL isolated from premenopausal women or postmenopausal women receiving estradiol replacement therapy stimulated eNOS, whereas HDL isolated from postmenopausal women did not stimulate eNOS. We conclude that HDL-associated estrodial is capable of the stimulating eNOS. These studies establish a new paradigm for examining the cardiovascular effects of HDL and estrogen.
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PMID:HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. 1275 Apr 8

Recent studies have reported that the activity of the calcium-dependent protease calpain is increased in acute inflammatory processes of the cardiovascular system. Because diabetes is associated with vascular inflammation, we hypothesized that increased calpain activity in response to hyperglycemia may play a role in diabetic cardiovascular disease. The effects of calpain inhibition on leukocyte-endothelium interactions induced by hyperglycemia were examined by intravital microscopy. Intraperitoneal administration of the selective calpain inhibitor benzyloxycarbonyl-leucyl-leucinal (5 micromol/L) prevented the up-regulation of leukocyte-endothelium interactions in response to 25 mmol/L D-glucose via a nitric oxide-dependent mechanism. Furthermore, treatment of rats with D-glucose significantly decreased basal endothelial NO release in mesenteric post-capillary venules, a phenomenon prevented by inhibition of calpain activity. Immunoprecipitation studies revealed that glucose induces loss of NO via a calpain-dependent decrease in the association of hsp90 with endothelial nitric oxide synthase. In addition, inhibition of calpain activity decreased endothelial cell surface expression of the pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 during hyperglycemia. These data demonstrate that calpains contribute to important inflammatory events during hyperglycemia and that pharmacological inhibition of calpain activity attenuates leukocyte-endothelium interactions and preserves eNOS function.
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PMID:A novel role for calpains in the endothelial dysfunction of hyperglycemia. 1282 89

Growth hormone deficiency is linked to cardiovascular disease and particularly increased peripheral vascular resistance. Surprisingly, its role in endothelial nitric oxide (NO) synthetase (eNOS) regulation and NO release is basically unknown. We therefore studied the effects of different doses of somatotropin in cultures of a human endothelial cell line (EAhy926). We investigated expression and activity of eNOS, as well as other target genes known to be deregulated in cardiovascular disease including E-selectin and the lectin-like oxidized low density lipoprotein receptor. Treatment of cultured human endothelial cells with somatotropin resulted in significant (P<0.05) increases of eNOS gene and protein expression, as well as NO release, whereas production of intracellular reactive oxygen species was significantly reduced, at the highest somatotropin dose level. The enhanced eNOS gene/protein expression and enzyme activity correlate well. Our findings are suggestive for a novel role of growth hormone in endothelial biology, and particularly NO production.
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PMID:Growth hormone induces eNOS expression and nitric oxide release in a cultured human endothelial cell line. 1467 75


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