Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparin cofactor II (HCII) is a serine proteinase inhibitor in human plasma that rapidly inhibits thrombin in the presence of dermatan sulfate or heparin. To understand the molecular mechanism for HCII deficiency in a patient with reduced circulating HCII antigen, we studied a Japanese patient with type I HCII deficiency who suffered from angina pectoris and coronary artery disease. Polymerase chain reaction (PCR)-based sequence analysis showed that the propositus' gene for HCII (HCII Awaji gene) had a thymine insertion after codon (GAT) for Asp88 in exon II, resulting in a frameshift mutation. Consequently, the abnormal HCII Awaji protein was suggested to have an altered amino acid sequence from position 89 and terminate at 107, thus being composed of the NH2-terminal one fifth of normal HCII and dysfunctional for thrombin inhibition. The molecular weight and pI value of HCII Awaji were calculated to be 12,040 and 3.6, respectively, without posttranslational modification. Mutagenic PCR followed by the Tsp509I digestion showed that a half of the PCR products derived from the propositus and his sister was cleaved, suggesting that his sister also has the same mutant allele. Crossed-immunoelectrophoresis and Western blot analyses of plasma and urine from the the propositus and of plasma from his sister did not provide evidence for the existence of the abnormal HCII, suggesting that little truncated HCII was circulating in the patient's blood. However, stable expression assay using human kidney 293 cells transfected with the expression vector containing cDNA encoding wild-type or Awaji-type HCII showed that mutant as well as wild-type HCII was secreted into culture medium normally. These results suggest that the abnormal HCII Awaji protein is secreted normally, but rapidly degraded in the circulating blood.
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PMID:Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor II Awaji). 856 24

The disturbances in coronary vasomotor tone have been extensively analyzed, but the exact molecular mechanisms underlying abnormal coronary vasomotion remain to be elucidated. It has been suggested that impaired coronary vasoreactivity can be the expression of a defect in vascular smooth muscle cells. A mouse model of human variant (vasospastic) angina has been recently obtained by disruption of Kir6.1/Kcnj8, a gene coding for a small pore-forming inward rectifier potassium channel. A phenotype resembling variant angina was also reported in mice lacking Sur2, the partner protein of Kir6.1. To better define the role of the smooth muscular ATP-sensitive potassium channels in the pathogenesis of abnormal coronary vasomotion, a complete mutational analysis of Kir6.1/KCNJ8 gene was performed in a series of 18 Italian patients with impaired coronary vasomotility. Polymerase chain reaction and direct sequencing of PCR products were done. No mutations were detected in the sample analyzed, thus suggesting that Kir6.1/KCNJ8 aberrations are not a common cause of abnormal coronary vasomotion in Italians. To the best of our knowledge, this study represents the first mutational analysis of Kir6.1/KCNJ8 gene in humans. Since major racial differences in the prevalence of abnormal coronary vasomotion have been described, further mutation screenings of Kir6.1/KCNJ8 gene are required to assess its role in the pathogenesis of impaired coronary vasomotility among various ethnic groups.
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PMID:Absence of Kir6.1/KCNJ8 mutations in Italian patients with abnormal coronary vasomotion. 1296 27

Because the endothelial nitric oxide synthase (eNOS) T-786C polymorphism is associated with reduced nitric oxide production and coronary artery spasm in Japanese patients, we speculated that it might be reversibly associated with Prinzmetal's variant angina in white Americans. Polymerase chain reaction analyses of eNOS T-786C and stromelysin 5A6A polymorphisms were done in 31 women and 12 men (42 white and 1 black American, median age 50 years), with well-documented Prinzmetal's variant angina. We matched each case with 1 healthy control by race and gender. Of the 43 cases, 21 (49%) were homozygous for wild-type normal eNOS, 19 (44%) were T-786C heterozygotes, and 3 (7%) were T-786C homozygotes. Of the 43 controls, 31 (72%) were homozygous for wild-type normal eNOS, 12 (28%) were T-786C heterozygotes, and 0 (0%) were T-786C homozygotes (p = .013). The mutant eNOS T-786C allele frequency in patients was 25 (29%) of 86 vs 12 (14%) of 86 in the controls (p = 0.016). Patients did not differ from controls for the distribution of the stromelysin 6A mutation (p = 0.66) or for the mutant 6A allele frequency (53% in cases, 50% in controls; p = 0.65). Nineteen patients took nitric oxide-elevating l-arginine (9.2 g/day, orally). Of these 19 patients, 10 (53%) became free of angina, 3 (16%) were improved but not angina free, and 6 (32%) had no change in their angina. Using l-arginine, the physical ability score (Seattle Angina Questionnaire) increased from a median of 42 to 72 of a total possible score of 100 (p = 0.011), satisfaction with symptom reduction increased from 53 to 61 (p = 0.004), and the perception of quality of life as acceptable increased from 29 to 50 (p = 0.001). In conclusion, the eNOS T-786C mutation appears to be a reversible etiology of Prinzmetal's variant angina in white Americans whose angina might be ameliorated by l-arginine.
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PMID:Endothelial nitric oxide synthase T-786C mutation, a reversible etiology of Prinzmetal's angina pectoris. 2021 21