No abstract

1. Doxorubicin (DOX), a standard chemotherapeutic anthracycline agent, causes a positive inotropic effect in guinea-pig isolated atria in a concentration-dependent manner with an ED(50) of 3.6 micromol/L. This increase in contractility is strictly related to the generation of reactive oxygen species (ROS) as a consequence of quinone metabolism. The ED(50) of DOX is significantly increased (P < 0.05) in the presence of 150 U superoxide dismutase (SOD). In the heart, DOX may be subjected to one- or two-electron reductions catalysed by flavoenzymes in the presence of suitable electron donors. Two-electron reduction is catalysed by NAD(P)H quinone acceptor oxidoreductase (DT-diaphorase; DTD). Whether DOX will be activated or detoxified by two-electron reduction is important for the understanding of the mechanism of both the toxic and antitumour actions of DOX. 2. In order to assess the role of DTD in cardiac responses to DOX, we examined the effect of both a specific inhibitor (dicoumarol) and an inducer (3-methylcholanthrene; MCA) of the enzyme on the inotropic action of DOX. 3. In guinea-pig isolated left atria, 4 micromol/L dicoumarol significantly enhanced the positive inotropic effect of DOX, especially at lower concentrations of DOX. In atria isolated from guinea-pigs treated with MCA (44 mg/kg, i.p. for 4 days), DTD activity was enhanced (approximately twice that of the control; P < 0.01), whereas the activity of glutathione S-transferase (GST) was not significantly altered. In these preparations, DOX caused a significantly lower increase in force of contraction than in atria isolated from untreated animals. 4. These results demonstrate that cardiac DTD does not contribute to ROS generation, but represents a detoxification system.

The p22phox protein subunit is essential for NADPH oxidase activity. The prevalence of C242T variants of p22phox gene was studied in 101 healthy Egyptian controls and 104 acute myocardial infarction (AMI) Egyptian patients. Contribution of oxidative stress, represented by serum oxidized-LDL (ox-LDL), in development of AMI was also examined and correlated with C242T gene variants. Genotyping and ox-LDL were assessed by PCR-RFLP and ELISA. Results showed that wild type CC genotype is prevalent in 27 % of controls; CT and TT are in 72 and 1 %. In patients, the distribution was 40.2, 59.8 and 0 % for CC, CT and TT; respectively, showing a significant difference (p = 0.0259). Serum ox-LDL levels were higher in patients than controls (p ≤ 0.0001). Subjects having CT genotype had lower levels of ox-LDL than CC genotype (p ≤ 0.005). C242T polymorphism of p22phox gene of NADPH oxidase is a novel genetic marker associated with reduced susceptibility to AMI.

The aim of this study was to detect endothelial nitric oxide synthase (eNOS) Glu298Asp gene variants in a random sample of the Egyptian population, compare it with those from other populations, and attempt to correlate these variants with serum levels of nitric oxide (NO). The association of eNOS genotypes or serum NO levels with the incidence of acute myocardial infarction (AMI) was also examined. Methods: One hundred one unrelated healthy subjects and 104 unrelated AMI patients were recruited randomly from the 57357 Hospital and intensive care units of El Demerdash Hospital and National Heart Institute, Cairo, Egypt. eNOS genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Serum NO was determined spectrophotometrically. Results: The genotype distribution of eNOS Glu298Asp polymorphism determined for our sample was 58.42% GG (wild type), 33.66% GT, and 7.92% TT genotypes while allele frequencies were 75.25% and 24.75% for G and T alleles, respectively. No significant association between serum NO and specific eNOS genotype could be detected. No significant correlation between eNOS genotype distribution or allele frequencies and the incidence of AMI was observed. Conclusion: The present study demonstrated the predominance of the homozygous genotype GG over the heterozygous GT and homozygous TT in random samples of Egyptian population. It also showed the lack of association between eNOS genotypes and mean serum levels of NO, as well as the incidence of AMI.

Serum asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), L-arginine, and C-reactive protein (hsCRP) levels were assessed in 100 Egyptian male 35-50-year-old patients with coronary artery disease (CAD), classified into: patients under conservative medical treatment, patients directed for percutaneous coronary interventions, patients directed for coronary artery bypass graft operation and patients suffering from acute myocardial infarction. Age- and sex-matched controls (n=100) were included. Correlation between serum levels of biomarkers and dimethylarginine dimethylaminohydrolase-2 (DDAH-2) genotypes was studied. No association between biomarkers and carriage of the specific DDAH2 SNP2 (-449C/G, rs805305) genotype was detected. Further studies are required to confirm the contribution of the biomarkers in the predisposition of CAD.