Dysfunction Coronary Artery Research Articles

Roles and Mechanisms of Human Immunodeficiency Virus Protease Inhibitor Ritonavir and Other Anti-Human Immunodeficiency Virus Drugs in Endothelial Dysfunction of Porcine Pulmonary Arteries and Human Pulmonary Artery Endothelial Cells

The objective of this study was to determine the effects of highly active antiretroviral therapy (HAART) drugs on pulmonary endothelial function. Porcine pulmonary arteries or human pulmonary arterial endothelial cells (HPAECs) were incubated with eight HAART drugs [ritonavir, indinavir, lopinavir, zidovudine (AZT), abacavir, stavudine, didanosine (ddI), and lamivudine] individually or in combination [three HAART drugs (3-plex; indinavir, stavudine, and ddI)] at their clinical plasma concentrations for 24 hours. Endothelium-dependent vasorelaxation in response to bradykinin was reduced significantly by the ritonavir in a concentration-dependent manner. Five other HAART drugs (indinavir, lamivudine, abacavir, AZT, and ddI) and the 3-plex significantly also impaired endothelium-dependent vasorelaxation in response to bradykinin. Five HAART drugs (ritonavir, indinavir, lamivudine, abacavir, and AZT) significantly decreased endothelial nitric oxide synthase (eNOS) expression and increased superoxide anion levels in both vessels and HPAECs. Furthermore, both ritonavir and AZT substantially activated ERK2 in HPAECs. Additionally, the antioxidants ginsenoside Rb1 and ginkgolide A effectively reversed HAART drug-induced vasomotor dysfunction and eNOS down-regulation. Inhibition of ERK1/2 also partially blocked ritonavir- and AZT-induced down-regulation of eNOS and vasomotor dysfunction. Thus, HAART drugs significantly impair endothelial functions of porcine pulmonary arteries and HPAECs, which may be mediated by eNOS down-regulation, oxidative stress, and ERK1/2 activation. These findings suggest that HAART drugs may contribute to the high incidence of pulmonary artery hypertension in human immunodeficiency virus-infected patients.

The Relationship Between Slow Coronary Flow and Angiotensin Converting Enzyme and ATIIR1 Gene Polymorphisms

Endothelial dysfunction in coronary arteries is the main pathogenetic mechanism in patients with slow coronary flow (SCF). Angiotensin converting enzyme (ACE) gene polymorphism has important effects on endothelial function. However, angiographic studies investigating the relation between the ACE and angiotensin II type 1 receptor (ATIIR1) insertion (I)/deletion (D) polymorphism and SCF is limited. Fifty-four patients with normal coronary arteries documented by coronary angiography with SCF in any coronary vessel, and 22 subjects with normal coronary arteries without SCF were included in this study. The ID (I/D), II, and DD genotypes were examined. Frequency of DD genotype was found higher in SCF group (50% vs. 27%, respectively; p = .055). Frequency of D allele was significantly higher in the SCF group (p < .05). Presence of DD genotypes increased the possibility of SCF 5.25 times compared to absence of DD genotype (OR, 5.25; 95% CI, 1.30-21.38, p < .05). There was no significant correlation of ATIIR1 gene polymorphism between the 2 groups. We demonstrated that DD genotype is a risk factor for SCF. Determination of ACE gene polymorphism in patients with SCF may be helpful in medical management and risk stratification.

Efficacy of Elective Intra-aortic Balloon Pump Therapy for High-Risk Off-Pump Coronary Artery Bypass: A Prospective Comparative Study

Objective:This study evaluated the usefulness of elective intra-aortic balloon pumping (IABP) in high-risk off-pump coronary artery bypass grafting (OPCAB). Materials and methods:From October 2002 through September 2006, total of 143 patients were operated with OPCAB. These patients were divided into two groups and clinical outcomes were compared: Group E (N = 30): Elective IABP group and Group C (N = 113): Control group, OPCAB without IABP. The criteria of elective application of IABP were severe stenosis of left main coronary artery (LMCA) or left ventricular dysfunction with an ejection fraction of less than 35%. Results:No significant difference was noted in the duration of ICU stay (Group E: 1.13 ± 0.43 days; Group C: 1.18 ± 0.60 days, p = 0.710), the number of patients on a respirator for 24 hours or longer after surgery (Group E: 10.0%; Group C: 5.3%, p = 0.397), hospital mortality (Group E: 0%; Group C: 0%), or the frequency of postoperative major complications between two groups. Conclusions:The outcomes of OPCAB using elective IABP in high-risk patients, such as those with severe LMCA stenosis or left ventricular dysfunction, were similar to those of OPCAB in low-risk patients, suggesting the usefulness of elective IABP in OPCAB.

Growth hormone–releasing peptide ghrelin inhibits homocysteine-induced endothelial dysfunction in porcine coronary arteries and human endothelial cells

Ghrelin, a novel growth hormone-releasing peptide, is implicated to play a protective role in cardiovascular tissues. However, it is not clear whether ghrelin protects vascular tissues from injury secondary to risk factors such as homocysteine (Hcy). This study investigated the effect and potential mechanisms of ghrelin on Hcy-induced endothelial dysfunction. Porcine coronary artery rings were incubated for 24 hours with ghrelin (100 ng/mL), Hcy (50 microM), or ghrelin plus Hcy. Endothelial vasomotor function was evaluated using the myograph tension model. The response to the thromboxane A(2)analog U46619, bradykinin, and sodium nitroprusside was analyzed. Endothelial nitric oxide synthase (eNOS) expression was determined using real-time polymerase chain reaction and immunohistochemistry staining, and superoxide anion production was documented lucigenin-enhanced chemiluminescence analysis. Human coronary artery endothelial cells (HCAECs) were treated with different concentrations of Hcy, ghrelin, or antighrelin receptor antibody for 24 hours, and eNOS protein levels were determined by Western blot analysis. Maximal contraction with U46619 and endothelium-independent vasorelaxation with sodium nitroprusside were not different among the four groups. However, endothelium-dependent vasorelaxation with bradykinin (10(-6) M) was significantly reduced by 34% with Hcy compared with controls (P < .05). The addition of ghrelin to Hcy had a protective effect, with 61.6% relaxation, which was similar to controls (64.7%). Homocysteine significantly reduced eNOS expression, whereas ghrelin cotreatment effectively restored eNOS expression to the control levels. Superoxide anion levels, which were increased by 100% with Hcy, returned to control levels with ghrelin cotreatment. Ghrelin also effectively blocked the Hcy-induced decrease of eNOS protein levels in HCAECs in a concentration-dependent manner. Antighrelin receptor antibody effectively inhibited the effect of ghrelin. Ghrelin has a protective effect in the porcine coronary artery by blocking Hcy-induced endothelial dysfunction, improving eNOS expression, and reducing oxidative stress. Ghrelin also shows a protective effect on HCACEs from the Hcy-induced decrease in eNOS protein levels. The effect of ghrelin is receptor-dependent. Thus, ghrelin administration may have beneficial effects in the treatment of vascular disease in patients with hyperhomocysteinemia.

Abstract 2567: Late Catch-Up Recovery from Endothelial Vasomotor Dysfunction in Infarct-Related Coronary Artery Treated with Sirolimus-Eluting Stent in Patients with Acute Myocardial Infarction

Myocardial ischemia-reperfusion causes endothelial injury in the infarct-related coronary artery. We have previously shown that sirolimus-eluting stent (SES) implantation can aggravate endothelium-dependent vasomotor dysfunction in infarct-related coronary arteries. This study examined effects of SES implantation on duration of reperfusion-induced endothelial dysfunction in infarct-related coronary arteries. This study enrolled 44 patients with a first acute myocardial infarction (AMI) due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy using SESs (n = 22) or bare metal stents (BMS, n = 22). Vasomotor function of LAD in response to acetylcholine (ACh) was repeated 2 weeks, 6 months, and 9 months after AMI. Patients with either residual stenosis or in-stent restenosis in LAD were not included in this study. The vasomotor function was also assessed in 20 control subjects for comparison with that in AMI patients. The SES and BMS groups were similar in terms of AMI-related variables including peak CK levels and 2 week LVEF. At 2 weeks after AMI, SES-treated LAD had greater impairment of epicardial dilation and less blood flow increase in response to ACh than BMS-treated LAD (diameter response; 12% vs. 34% of controls, blood flow response; 23% vs. 76% of controls, at 10 μg/min of ACh, respectively). In BMS-treated LAD, the responses of epicardial diameter and blood flow to ACh had recovered to levels similar to those of controls at 6 months (diameter response; 94% of controls, blood flow response; 92% of controls), and the responses showed no further improvement from 6 to 9 months. In SES-treated LAD, the responses were improved but remained lowered compared with BMS-treated LAD at 6 months (diameter response; 58% of controls, blood flow response; 74% of controls). However, the responses in SES-treated LAD at 9 months showed further improvement to levels near to those of BMS-treated LAD or controls (diameter response; 79% of controls, blood flow response; 88% of controls). Although incomplete, the adverse effects of SES on endothelium-dependent vasomotor function in infarct-related coronary arteries were restored through late catch-up recovery after stent implantation.

Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells

The objective of this study was to determine the effects and mechanisms of serum amyloid A (SAA) on coronary endothelial function. Porcine coronary arteries and human coronary arterial endothelial cells (HCAECs) were treated with SAA (0, 1, 10, or 25 microg/ml). Vasomotor reactivity was studied using a myograph tension system. SAA significantly reduced endothelium-dependent vasorelaxation of porcine coronary arteries in response to bradykinin in a concentration-dependent manner. SAA significantly decreased endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein levels as well as NO bioavailability, whereas it increased ROS in both artery rings and HCAECs. In addition, the activities of internal antioxidant enzymes catalase and SOD were decreased in SAA-treated HCAECs. Bio-plex immunoassay analysis showed the activation of JNK, ERK2, and IkappaB-alpha after SAA treatment. Consequently, the antioxidants seleno-l-methionine and Mn(III) tetrakis-(4-benzoic acid)porphyrin and specific inhibitors for JNK and ERK1/2 effectively blocked the SAA-induced eNOS mRNA decrease and SAA-induced decrease in endothelium-dependent vasorelaxation in porcine coronary arteries. Thus, SAA at clinically relevant concentrations causes endothelial dysfunction in both porcine coronary arteries and HCAECs through molecular mechanisms involving eNOS downregulation, oxidative stress, and activation of JNK and ERK1/2 as well as NF-kappaB. These findings suggest that SAA may contribute to the progress of coronary artery disease.

Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic db/db Mice

We previously showed epidermal growth factor receptor (EGFR) transactivation to be key mechanism in the regulation of resistance artery myogenic tone. Type 2 diabetes is associated with microvascular complications. We hypothesized that elevated EGFR phosphorylation contributes to resistance artery dysfunction in type 2 diabetes. Diabetic db/db and nondiabetic (control) mice were treated with EGFR inhibitor (AG1478; 10 mg x kg(-1) x day(-1)) for 2 weeks. Isolated coronary artery and mesenteric resistance artery (MRA) were mounted in an arteriograph. Pressure-induced myogenic tone was increased in MRA and coronary artery from diabetic mice and normalized by AG1478. Phenylephrine-induced contraction and nitric oxide donor-induced relaxation were similar in all groups. Endothelium-dependent relaxation in response to shear stress and acetylcholine of MRA and coronary artery from diabetic mice was altered and associated with reduced endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Treated diabetic mice with AG1478 improved coronary artery and MRA endothelial function and restored eNOS expression. Immunostaining and Western blot analysis showed increased endothelial and smooth muscle cell EGFR phosphorylation of MRA and coronary artery from diabetic mouse, which was reduced by AG1478. Primary cultured endothelial cells from resistance arteries treated with high glucose for 48 h showed an increase of EGFR phosphorylation associated with eNOS expression and phosphorylation decrease in response to calcium ionophore. Pretreatment of endothelial cells with AG1478 prevented the effect of high glucose. This study provides evidence of the role of elevated EGFR phosphorylation in coronary artery and MRA dysfunction in diabetic db/db mice. Therefore, EGFR should be a potential target for overcoming diabetic small artery complications.

Increased activation of BKCa channels prevents endothelial dysfunction in coronary arteries from ouabain‐induced hypertensive rats

Chronic ouabain administration induces hypertension. The aim of this study was to compare the endothelium‐dependent relaxation in coronary arteries (CA) isolated from ouabain‐treated versus non‐treated Wistar rats. In 5HT precontracted arteries, acetylcholine (Ach) induced similar relaxant responses in CA from both groups, and this relaxant effect was abolished by the nitric oxide synthase inhibitor L‐NAME. However, when arteries were contracted with high KCl or preincubated with the BKCa channel inhibitor iberiotoxin, but not with the Kv channel blocker 4‐aminopyridine, the relaxation elicited by Ach was more reduced in ouabain‐treated than control rats. Similar results were obtained with the NO donor DEA‐NO in endothelium‐denuded CA. In CA myocytes isolated from ouabain‐treated, but not from non‐treated rats, addition of DEA‐NO (1 μM) markedly increased the amplitude of the iberiotoxin‐sensitive current in the whole range of test potentials. This effect was prevented by the soluble guanylate cyclase inhibitor ODQ. Our results suggest that an increased activation of BKCa channels by NO prevents endothelial dysfunction in CA from ouabain‐treated rats. Supported by AGL2004‐06685/ALI, SAF2005‐03770, Fundacion Mutua Madrileña, SAF2006‐02376 and RECAVA RD06/0014/0011

Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes

Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats, a model of the metabolic syndrome, and Zucker Diabetic Fatty (ZDF) rats, a model of type 2 diabetes. Because of their lipid lowering action and antioxidant activity, we predicted that treatment with Rosuvastatin, an HMG-CoA reductase inhibitor (statin) or Enalapril, an angiotensin converting enzyme (ACE) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes. Methods 20-week-old Zucker obese and 16-week-old ZDF rats were treated with Rosuvastatin (25 mg/kg/day) or Enalapril (20 mg/kg/day) for 12 weeks. We examined metabolic parameters, indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries (75–175 µm intraluminal diameter) from lean, Zucker obese and ZDF rats (untreated and treated). Results Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats. Both drugs improved metabolic parameters, oxidative stress, and vascular dysfunction in Zucker obese rats, however, only partial improvement was observed in ZDF rats, suggesting more aggressive treatment is needed when hyperglycemia is involved. Conclusion Vascular dysfunction is improved when Zucker obese and, to a lesser degree, when ZDF rats were treated with Rosuvastatin or Enalapril.

Sirolimus-Eluting Stent Implantation Aggravates Endothelial Vasomotor Dysfunction in the Infarct-Related Coronary Artery in Patients With Acute Myocardial Infarction

This study examined whether sirolimus-eluting stent (SES) implantation may affect endothelial vasomotor dysfunction in resistance and epicardial infarct-related coronary arteries in acute myocardial infarction (AMI). Myocardial ischemia-reperfusion causes endothelial injury entirely in the vasculature of the infarct-related coronary artery. Sirolimus-eluting stent implantation inhibits re-endothelialization at the site of stenting. This study included 29 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy using a SES (n = 13) or bare-metal stent (BMS) (n = 16). The diameter of the epicardial segment distal to the site of SES deployment and coronary blood flow in the LAD in response to an intracoronary infusion of acetylcholine were measured at 2 weeks after AMI. Levels of vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunoadsorbent assay in plasma obtained from the aortic root (AO) and the anterior interventricular vein (AIV) in all patients. The epicardial coronary artery was more severely constricted in response to acetylcholine in the SES than in the BMS group. The increase in coronary blood flow in response to acetylcholine was lower in the SES than in the BMS group. Vascular endothelial growth factor levels in the AIV were significantly lower than in the AO in the SES group but not in the BMS group. During the course of AMI, SES implantation adversely affects endothelium-dependent vasomotor function in resistance and epicardial coronary arteries after the ischemia-reperfusion in association with a reduction in myocardial VEGF secretion.

Association of paraoxonase activity and coronary blood flow

Background Paraoxonase (PON) is a high-density lipoprotein-bound anti-oxidant enzyme that inhibits atherosclerosis and endothelial dysfunction. Slow coronary flow (SCF) has long been identified and endothelial dysfunction and atherosclerosis of epicardial coronary arteries and microvasculature were reported to be associated with SCF. Consequently, we aimed to investigate the association between coronary blood flow by means of Thrombolysis in Myocardial Infarction frame count (TFC) and serum PON activity and other laboratory parameters in patients with SCF compared to control cases. Methods Twenty-four patients with SCF and 110 control cases with normal coronary flow were studied after quantifying coronary blood flow according to TFC. Serum PON activity was evaluated by measuring the rate of paraoxon hydrolysis. The association between TFC and serum PON activity and other clinical and laboratory parameters were evaluated. Results There were statistically significant differences between SCF and control groups in respect to serum uric acid ( p = 0.001), high sensitive C-reactive protein ( p = 0.03) levels and serum PON activity ( p < 0.001). The mean TFC was correlated with male gender ( r = 0.263, p = 0.002), serum uric acid level ( r = 0.287, p = 0.001), hemoglobin concentration ( r = 0.192, p = 0.032) and serum PON activity ( r = −0.306, p < 0.001). Serum uric acid level ( χ 2 = 10.08, β = 0.362, p = 0.009) and serum PON activity ( χ 2 = 16.73, β = −0.005, p = 0.001) were independent predictors of SCF whereas the only independent predictor of mean TFC was serum PON activity ( β = −0.318, p < 0.001). Conclusion These findings suggest that serum PON activity is independently associated with mean TFC and reduced serum PON activity might represent a biochemical marker of SCF.

P289: Growth-related oncogene alpha (GRO-alpha) induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells

P289: Growth-related oncogene alpha (GRO-alpha) induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells

Statin or ACE Inhibitor Improve Vascular Dysfunction in Zucker Obese and ZDF Rats

Previous studies have shown vascular dysfunction in small coronary and mesenteric arteries from Zucker obese and Zucker Diabetic Fatty (ZDF) rats. Our hypothesis is that treatment with HMG-CoA reductase inhibitor (statin) or angiotension converting enzyme inhibitor (ACEi) will improve vascular dysfunction in these rat models. Zucker obese and ZDF rats were treated with Rosuvastatin (50mg/Kg/day) or Enalapril (40mg/Kg/day) for 12 weeks. We examined small ventricular and mesenteric vessels using an isolated vessel preparation. Acetylcholine (Ach, 10-10–10-4 M) dilation was evaluated after U46619 constriction. Results: % Relaxation to 10 ?M Ach, (n). Ach responses were attenuated in both vascular beds from Zucker obese and ZDF rats compared to vessels from lean rats. Ach responses were augmented in vessels from statin or ACEi treated rats, compared to vessels from untreated rats. Endothelial dysfunction was improved when Zucker, and to a lesser degree when ZDF rats were treated with statin or ACEi suggesting more aggressive therapy is needed when hyperglycemia is involved. Supported by VA Merits to Drs. Oltman and Yorek.

Different effects of statin treatment on endothelial dysfunction in the coronary and carotid arteries of hypercholesterolemic pigs

Different effects of statin treatment on endothelial dysfunction in the coronary and carotid arteries of hypercholesterolemic pigs

Coronary flow reserve is also impaired in patients with subclinical hypothyroidism

The diagnosis of subclinical hypothyroidism and detection of its effects on cardiovascular system is important. Also, the patients with subclinical hypothyroidism even at the very early stage are at increased risk for developing atherosclerosis. We evaluated coronary microvascular circulation and endothelial dysfunction of epicardial coronary arteries by the measurement of coronary flow velocity reserve via a non invasive technique, transthoracic Doppler echocardiography in subclinical hypothyroidism. Coronary flow reserve in patients with subclinical hypothyroidism such as in overt hypothyroidism was lower than that of euthyroid subject. As a conclusion, endothelial and microvascular dysfunction, which are early harbingers of atherosclerosis, are shown in overt and subclinical hypothyroidism.

Temporary coronary artery occlusion during off-pump coronary artery bypass grafting with the new poloxamer P407 does not cause endothelial dysfunction in epicardial coronary arteries

The aim of this study was to assess the efficacy of the novel reversible thermosensitive gel poloxamer 407 for occlusion of the coronary vessel necessary for minimally invasive operations and its effects on coronary endothelium. Domestic swine were submitted to occlusion of the left anterior descending or right coronary artery using the poloxamer. The left and right internal thoracic arteries were used as grafts to perform coronary artery bypasses. Animals were humanely killed after 3 hours of perfusion (acute; n = 8) or 3 days (subacute; n = 6). The vascular reactivity of coronary artery was evaluated in response to serotonin and bradykinin. Histologic studies were performed to analyze cardiomyocyte necrosis and endothelial coverage. The gel led to an occlusion of 7.8 +/- 2.2 minutes. Concentration-response curves of occluded coronary segments showed no difference of endothelium-dependent relaxations in both operated groups (P < .05 vs control). Histologic studies demonstrated the absence of cardiomyocyte necrosis after coronary artery occlusion in the acute group; a small infarct zone was detected in 1 animal in the subacute group, resulting from an occlusion of the first diagonal branch. The endothelial layer coverage was preserved in both groups. The poloxamer 407 represents a promising technique for obtaining hemostasis at the site of anastomosis during construction of bypasses during beating heart coronary artery surgery, without damage to the endothelium or ischemic consequence.

Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries

Homocysteine is an independent risk factor for atherosclerosis. The objective of this study was to investigate whether ginkgolide A (GA), a major constituent of Ginkgo biloba, could block homocysteine-induced endothelial dysfunction in porcine coronary arteries. Porcine coronary artery rings were assigned to six treatment groups: control; homocysteine (50 micromol/L); low-dose (50 micromol/L) or high-dose (100 micromol/L) GA; and homocysteine plus low-dose or high-dose GA. After 24 hours' incubation, the rings were analyzed for vasomotor function in response to a thromboxane A2 analogue (U46619), bradykinin, and sodium nitroprusside. Endothelial nitric oxide synthase (eNOS) was studied by using real-time polymerase chain reaction and immunohistochemistry analysis. Superoxide anion production was assessed by chemoluminescence analysis. Endothelium-dependent relaxation (bradykinin) was significantly reduced in ring segments treated with homocysteine as compared with the control (P < .05). When homocysteine was combined with either low-dose or high-dose GA, endothelium-dependent relaxation was markedly recovered. There was no significant difference in maximal contraction (U46619) or endothelium-independent relaxation (sodium nitroprusside) among all groups. In addition, superoxide anion production was increased by 113% in the homocysteine-treated group, whereas there was no statistically significant difference between the control and GA/homocysteine groups. Furthermore, eNOS messenger RNA and protein levels were substantially reduced in the homocysteine-treated group (P < .05), but not in the GA/homocysteine combined groups. Homocysteine significantly impairs endothelium-dependent vasorelaxation through oxidative stress and downregulation of eNOS in porcine coronary arteries. GA effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores the potential clinical benefits and applications of GA in controlling homocysteine-associated vascular injury and cardiovascular disease. Homocysteine is an independent risk factor for atherosclerosis. This study showed that ginkgolide A, a major constituent of Ginkgo biloba, effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores potential clinical benefits and applications of ginkgolide A in controlling homocysteine-associated vascular injury and cardiovascular disease.

Roads to Dysfunction

See related article, pages 951–960 Oxidized low-density lipoprotein (oxLDL) is considered to be the strongest proatherogenic lipoprotein. OxLDL is rapidly taken up by endothelial cells and macrophages and via the steps of foam cell formation and cell death, oxLDL eventually accumulates in the lipid core of atherosclerotic plaques.1 The interaction of oxLDL with cells is mediated by several receptors.2 Members of the scavenger receptor family predominate in macrophages,3 whereas endothelial cells mainly take up oxLDL by the lectin-like ox-LDL receptor-1 (LOX-1).4 On binding to LOX-1, oxLDL activates a multitude of signaling cascades involving MAP kinases,5,6 protein kinase C (PKC),7,8 and protein kinase B9 in endothelial cells. The consequence of this cellular activation, is apoptosis and superoxide anion production, the latter originating from the NADPH oxidase and uncoupling of the endothelial NO synthase (eNOS). OxLDL therefore is a strong inducer of endothelial dysfunction, a state in which the endothelium, instead of generating NO, produces superoxide anions. OxLDL also modulates the specific activity of NOS. It increases caveolin I expression and the interaction of NOS with this protein impairs NO production.10 Furthermore, oxLDL modulates PKC activity and expression and this family of kinases has been shown to acutely attenuate eNOS-dependent NO production and to promote eNOS uncoupling during prolonged exposure times.11 Several observations suggest that the supply of eNOS with the substrate l-arginine is impaired in the presence of oxLDL: In hypercholesterolemia, supplementation of l-arginine improves endothelium-dependent relaxation and NO production;12,13 l-arginine also attenuates the development of atherosclerosis,14 and normalizes leukocyte adhesion …

Effect of tetrahydrobiopterin on selective endothelial dysfunction of epicardial porcine coronary arteries induced by cardiopulmonary bypass

We hypothesized that cardiopulmonary bypass induces a selective alteration of the coronary arterial endothelial cell signal transduction which could be explained by a state of depletion and/or decreased activity of endogenous tetrahydrobiopterin (BH(4)). The aim of this study was to assess the effects of cardiopulmonary bypass and BH(4) on the endothelial function of epicardial coronary arteries in a swine model of cardiopulmonary bypass. Swine underwent 90 min of cardiopulmonary bypass alone (N=19) or in association with a brief cardioplegic arrest with (N = 6) or without (N = 5) in vivo BH(4) administration, followed by a 60-min period following weaning from cardiopulmonary bypass and were compared to a control group (N = 7). Endothelium-dependent relaxations of epicardial coronary artery rings were studied using standard organ chamber experiments in the presence or absence of in vitro BH(4) or superoxide dismutase (SOD) and catalase. Cardiopulmonary bypass caused a statistically significant reduction of endothelium-dependent relaxations to serotonin (p < 0.0001), bradykinin (p < 0.001), UK14304 (p < 0.0001) and calcium ionophore (p < 0.01) in epicardial porcine coronary arteries. In vitro and in vivo BH(4) supplementation improved endothelium-dependent relaxations to serotonin and bradykinin, which were left unchanged by SOD-catalase administration. Cardiopulmonary bypass was associated with a decrease in nitric oxide availability (p = 0.002) and increased oxidative stress (p < 0.001), which were both restored by in vivo BH(4) administration (p < 0.001). Treatment with BH(4) improves the endothelial dysfunction of porcine epicardial coronary arteries, restores nitric oxide availability and reduces the oxidative stress associated with cardiopulmonary bypass.

COX-2, Another Important Player in the Nitric Oxide–Endothelin Cross-Talk

See related article, pages 1439–1445 Traditionally, the role of the endothelium was thought to be primarily that of a selective barrier to the diffusion of macromolecules from the vessel lumen to the interstitial space. During the past 20 years, numerous additional roles for the endothelium have been defined such as regulation of vascular tone, modulation of inflammation, promotion as well as inhibition of vascular growth, and modulation of platelet aggregation and coagulation. Endothelial dysfunction is a characteristic feature of patients with cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and chronic smoking. More recent studies indicate that it may predict long-term atherosclerotic disease progression as well as cardiovascular event rate.1 There is a growing body of evidence that decreased endothelial bioavailability of nitric oxide (NO·) in particular attributable to increased production of reactive oxygen species, such as superoxide (O2·−), leads to an activation of the renin–angiotensin system,2,3 increased formation of cyclooxygenase (COX)-dependent vasoconstrictors,4 but also to increased expression of the most potent endogenous vasoconstrictor endothelin-1 (ET-1).5–9 Of the 4 active endothelins (ET-1 to ET-4) ET-1 is the predominant isoform in the cardiovascular system. ET-1 exerts its major cardiovascular effects through activation of 2 distinct G protein–coupled receptors, the ETA and ETB receptors. ETA receptors are found exclusively in smooth muscle cells. Endothelin-1 promotes vasoconstriction, mitogenesis, and thrombosis predominantly via binding to the ETA receptor. ETB receptors are localized to some extent in smooth muscle cells, but also in endothelial cells. Activation of ETB receptors has been demonstrated to cause the release of NO· and prostacyclin (PGI2).10,11 In normal states with p reserved vascular (endothelial) NO …