Hypoxia-inducible factor-1α polymorphisms link to coronary artery collateral development and clinical presentation of coronary artery disease.

AIMS: This study aimed to investigate the association of Hypoxia-inducible factor-1α (HIF-1α) C1772T and G1790A single nucleotide polymorphisms (SNPs) with: incidence, clinical type, severity of coronary atherosclerosis and coronary collaterals of coronary artery disease (CAD). METHODS: The clinical data and genomic DNA were gathered in 958 subjects, including 560 controls and 398 patients with CAD. CAD was confirmed with coronary angiography (CAG). The genotypes for two SNPs were determined by high resolution melting after PCR amplification. RESULTS: Neither the HIF-1α C1772T nor the G1790A genotype was significantly associated with CAD and, no gene-gene or gene-environmental interactions were identified. However, both HIF-1α C1772T and G1790A (P<0.05) alleles were associated with clinical type and formation of coronary collaterals (P<0.05). Patients carrying genotype CT (P=0.019, OR=4.905,91, 95% CI: 1.355-17.761) and GA (P=0.026, OR=3.052, 95% CI: 1.180-7.892) had significantly higher stable angina pectoris (SAP) than unstable angina pectoris (UAP) and acute myocardial infarction (AMI). The presence of HIF-1 genotype CT (P=0.016, OR=13.373, 95% CI: 15.468-32.709) and GA (P=0.001, OR=19.741, 95% CI: 8.125-47.966) predicted lower collateral formation and severity of CAD secondary to the absence of collaterals (r=0.242, P<0.001). CONCLUSIONS: We conclude that functional polymorphisms in the HIF-1α gene do not modify CAD risk but they are associated with the formation of coronary collaterals and clinical presentation of CAD.

Expression of heme oxygenase-1, hypoxia inducible factor-1alpha, and ubiquitin in peripheral inflammatory cells from patients with coronary heart disease.

BACKGROUND: The increased expression of heme oxygenase-1 content, a stress-response protein, directly correlates with the incidence of coronary heart disease. Down-regulation of hypoxia inducible factor-1alpha activity, a major downstream effector of the signaling pathways activated by hypoxia, increases cell survival after hypoxia. The ubiquitin system, a non-lysosomal pathway of protein degradation, is involved in processes of coronary heart disease. The aim of this study was to investigate the expression of heme oxygenase-1, hypoxia inducible factor-1alpha, and ubiquitin in both monocytes and lymphocytes isolated from patients at the mRNA and protein levels in different stages of coronary heart disease and their possible correlation. METHODS: A total of 90 patients with coronary heart disease (30 acute myocardial infarction, 30 unstable angina pectoris, and 30 stable angina pectoris) were selected, and 30 cases with normal coronary artery served as controls. The mRNA and protein expression of heme oxygenase-1, hypoxia inducible factor-1alpha, and ubiquitin in monocytes and lymphocytes were examined by semi-quantitative reverse transcriptase polymerase chain reaction and Western blotting, respectively. RESULTS: The mRNA expression of heme oxygenase-1 and ubiquitin was associated with the severity of coronary heart disease (p<0.05). There was no significant difference in hypoxia inducible factor-1alpha mRNA expression between the coronary heart disease patients and controls. The protein expression of heme oxygenase-1, hypoxia inducible factor-1alpha, and ubiquitin was significantly stronger in patients with coronary heart disease than in controls, and the expression levels increased with the severity of the disease. There was a positive association between heme oxygenase-1 and hypoxia inducible factor-1alpha and ubiquitin, antioxidative therapy with adrenergic receptor blocker, angiotensin-converting enzyme inhibitor or statins up-regulated the expression of heme oxygenase-1 and hypoxia inducible factor-1alpha. CONCLUSIONS: These data suggest that heme oxygenase-1, hypoxia inducible factor-1alpha, and ubiquitin are involved in the development and progression of coronary heart disease and thus may be useful biomarkers for coronary heart disease.

Hypoxia-inducible factor-1alpha induces the coronary collaterals for coronary artery disease.

BACKGROUND: Marked variability exists in coronary artery collaterals in patients with ischemic heart disease. Multiple factors are thought to play a role in collateral development; however, the contribution of hypoxia inducible factor-1alpha (HIF-1alpha), which is a transcriptional activator that functions as a master regulator of oxygen homeostasis, is not completely clear. It could play an important role in modulating collateral development. OBJECTIVE: The objective of this study is to investigate the changes and significance of expression of HIF-1alpha in patients with coronary artery collaterals. METHODS: Collateral vessels were determined in 98 patients with >or=70% narrowing of at least one coronary artery without earlier revascularization, 42 patients with coronary artery collaterals and 56 patients with no coronary artery collaterals. Extent of collaterals was expressed as scores according to the Rentrop scoring system. Another 50 cases with normal coronary arteries were selected as control. The levels of HIF-1alpha protein expression in monocyte and lymphocyte in the participants were tested by immunohistochemistry (IHC) and western blot; mRNA levels were measured using reverse transcriptase PCR technique. RESULTS: Compared with the control with normal coronary artery, the patients had higher expression of HIF-1alpha protein tested by IHC and western blot (52.6+/-10.2 vs. 13.7+/-6.2 by IHC, 50.8+/-4.5 vs. 6.5+/-1.8 by western blot); furthermore, significantly higher HIF-1alpha expression was observed in patients with collaterals compared with patients with no collaterals (81.5+/-11.8 vs. 20.7+/-9.4 by IHC; 87.2+/-6.5 vs. 9.5+/-1.4 by western blot). On the transcriptional levels of HIF-1alpha, the result was the same as the protein, there was significant difference of HIF-1alpha between the three groups. The patients with collaterals were the highest (127.3+/-23.9), followed by patients with no collaterals (35.7+/-12.3), and the control were the lowest (23.5+/-9.3). A highly positive correlation was observed between the expression/transcription of HIF-1alpha and collateral score (P<0.01, IHC: r1=0.78, reverse transcriptase PCR: r2=0.69, western blot: r3=0.84). CONCLUSION: These data suggest that higher inductions of HIF-1alpha are associated with coronary collaterals, thus implying that HIF-1alpha may promote coronary collateral formation. Detection of HIF-1alpha expression might be helpful to predict prognosis of patients with coronary artery disease.

Haem oxygenase-1 expression and coronary heart disease--association between levels of haem oxygenase-1 expression and angiographic morphology as well as the quantity of coronary lesions.

OBJECTIVE: The aim of this paper was to investigate the association between levels of HO-1 expression and angiographic morphology as well as the quantity of coronary lesions in patients with coronary heart disease (CHD). METHODS: 110 patients with CHD were diagnosed by coronary angiography which contained coronary lesions in some way. Firstly, the patients were divided into 3 groups according to the angiographic morphology of their coronary lesions: type I (smooth borders) group (n1= 36), type II (irregular borders) group (n2= 48) and type III (long and irregular lesions) group (n3= 26). Secondly, the patients were split into a further 3 groups, named: single-vessel group (SV, 38 cases), double-vessel group (DV, 44 cases) and multi-vessel group (MV, 28 cases) according to the number of coronary lesions. Another 30 patients with normal coronary arteries (diagnosed by coronary angiography) were selected as the control group. The levels of HO-1 protein expression in monocytes and lymphocytes from the subjects were tested by immunohistochemistry and Western blot. A computer picture analysing system was also used to measure the levels of HO-1 protein expression. RESULTS: HO-1 protein was located in cell plasma and the levels of HO-1 protein expression in patients with CHD were significantly higher than in those without CHD (p < 0.01). There were significant differences of HO-1 expression among patients with CHD. Patients with type III lesions had the highest levels, followed by those with type II lesions and the lowest levels were found in patients with type I lesions (p < 0.01). Also, levels of HO-1 protein expression in patients with multi-vessel disease and double-vessel disease were significantly higher than in those with single-vessel disease (p < 0.01). CONCLUSIONS: There is a higher expression of HO-1 in patients with CHD and the levels of HO-1 protein are associated with severity of CHD angiographically.

[Clinical study on changes of heme oxygenase-1 expression in patients with acute myocardial infarction].

OBJECTIVE: To investigate changes in heme oxygenase-1(HO-1) in patients with acute myocardial infarction. METHODS: Forty-five patients with acute myocardial infarction and 50 with coronary heart disease (diagnosed by coronary angiography) but without acute myocardial infarction were included in this study, and another 40 patients with normal coronary artery as controls. Levels of HO-1 protein expression in monocyte and lymphocyte isolated from the patients were determined by immunohistochemistry and Western blot. Computer picture analyzing system was also used to measure levels of HO-1 protein expression. RESULTS: HO-1 protein expression was located in the cytoplasm. The levels of HO-1 protein expression in patients with acute myocardial infarction were significantly higher than those without acute myocardial infarction (P<0.01). In addition, low levels of HO-1 protein expression were observed in patients with normal coronary artery. CONCLUSION: There is a higher expression of HO-1 in patients with acute myocardial infarction, and a lower expression in patients with normal coronary artery.