Saudi Cultural Missions Theses & Dissertations
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Item Restricted Efficiency of Nitric Oxide and Peroxynitrite Release by Endothelial Nitric Oxide Synthase Variants - Implications for Cardiovascular Disease and Aging(Ohio University, 2024-05) Alsulami, Seham; Malinski, Tadeusz; Dewald, HowardThe cardiovascular system is mainly regulated by nitric oxide (NO). A reduction in its synthesis or bioavailability might underlie the impaired endothelium-dependent vasodilatation, which is observed in the blood vessels of individuals with cardiovascular disease (CVD). The dysfunction of endothelium, which is a main characteristic of vascular aging, has been associated with low NO production and high production of cytotoxic peroxynitrite (ONOO-). Thus, the ratio of NO to ONOO- is an indicator of endothelial dysfunction. Moreover, vascular NO is produced by an enzyme called (endothelial nitric oxide synthase (eNOS), and its gene exhibits high polymorphism. However, it is unclear whether polymorphisms or haplotypes in the eNOS gene affect the NO production, ONOO- production, and eNOS coupling, as well as how aging impacts these haplotypes. The influence of the eNOS haplotype (consisting of single nucleotide polymorphisms (SNP) in the promoter region (T-786C) and (C-665T) and exon 7 (Glu298Asp) and a variable number of tandem repeats (VNTR) in intron 4 (4a/4b/4c)) on the production of NO and ONOO- and eNOS coupling was investigated. Sanger sequencing and DNA electrophoresis were used to detect SNPs and VNTRs in the samples, respectively. To evaluate the production of NO and ONOO-, nanosensors were used to determine the maximal concentrations of NO and ONOO- and traditional and low-temperature SDS-PAGE to evaluate the expression of eNOS and the eNOS dimer/monomer ratio, respectively. Interestingly, these results indicated that the eNOS haplotype (H5) combining the “T T/C C 4b” of the G894T, T-786C, C-665T, and 27 bp VNTR a/b/c is more susceptible to endothelial dysfunction. Compared with other haplotype samples, it had lower [NO]/[ONOO-] and higher eNOS expression with reduced eNOS dimer/monomer (P < 0.005). These findings have important implications for understanding the genetic basis of cardiovascular disease and aging and may lead to new therapeutic approaches to these diseases.37 0