Genetic predisposition in patients with hypertension and normal ejection fraction to oxidative stress

Abstract

The role of oxidative stress (OXS) due to myocardial nitric oxide synthase (NOS) uncoupling related to oxidative depletion of its cofactor tetrahydrobiopterin (BH 4 ) emerged in the pathogenesis of heart failure with preserved ejection fraction (HFPEF).We determined the prevalence of 6 single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to OXS, BH 4 metabolism and NOS function in >60-year-old 94 patients with hypertension and 18 age-matched controls with normal EF. Using echocardiography 56/94(60%) patients with hypertension had left ventricular (LV) diastolic dysfunction (HTDD+ group), 38/94(40%) patients had normal LV diastolic function (HTDDgroup). Four SNPs (rs841, rs3783641, rs10483639, rs807267) of guanosine triphosphate cyclohydrolase-1, the rate limiting enzyme in BH 4 synthesis, 1 (rs4880) of manganese superoxide dismutase, and 1 (rs1799983) of endothelial NOS genes were genotyped using real time PCR method and Taqman probes. Protein carbonylation (PC), BH 4 and total biopterin levels were measured from plasma samples. No between-groups difference in minor allele frequency (MAF) of SNPs was found. We calculated a genetic score indicating risk for OXS based on the MAFs of the SNPs. A high genetic risk for OXS was significantly associated with HTDD+ even after adjustment for confounding variables [OR(95%CI):4.79(1.12-20.54); p=0.035]. In both patient groups PC (p<0.05 for both), plasma BH 4 (p<0.01 for both) and in the HTDD+ group total biopterin (p<0.05) increased vs. controls. In conclusion, in patients with hypertension and normal EF, a potential precursor of HFPEF, a partly genetically determined increased OXS seems to be associated with the presence of LV diastolic dysfunction.key words: hypertension, heart failure with preserved ejection fraction, oxidative stress 3

Redox Stress Defines the Small Artery Vasculopathy of Hypertension

“…MTHFR , which encodes methylenetetrahydrofolate reductase, and SH2B3 , which regulates cell differentiation, may influence cellular redox states indirectly. Recent studies indicate a high genetic risk of oxidative stress in hypertensive patients, evidenced by increased prevalence of SNPs of genes encoding enzymes related to oxidative stress (guanosine triphosphate cyclohydrolase-1 involved in BH4 synthesis, mSOD and eNOS) (4). Together genes regulating vascular function and oxidative stress seem to track with hypertension.…”

Superoxide dismutase gene polymorphism is associated with ischemic stroke risk in the Chinese Han population

“…from the cytoplasm to the mitochondria, and β folding affected the proper identification of the signal peptides and related receptors on the mitochondrial inner membrane, and exhibited reduced the transcriptional activity of SOD2 to the mitochondria by 30-40% affect the entry of SOD2 into mitochondria to play an antioxidant role, which increased the risk of coronary artery disease [25].Mutations in the SOD2 gene increase the risk of developing cancer, SOD2 SNP rs4880 (T > C) resulted in conformational changes of the protein helix structure, an increased risk of oral cancer, and has been linked to a variety of others cancers [26]. Studies have shown that rs4880 SNP (T > C changes at the nucleotide level) at codon 16 causes alanine (GCT) to replace valine (GTT) [27].…”

Up-to-date clinical approaches of biomarkers’ use in heart failure

“…Indeed, (Berezin, 2016d;Fazakas et al, 2016;Friedrich et al, 2013;Hofman et al, 2010;Kolder et al, 2012;McNamara et al, 2014;Sutter et al, 2013). As biomarkers particularly used to scrutiny single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to oxidative stress (Berezin, 2016e), genotype of guanine nucleotide-binding proteins (G-proteins) beta-3 subunit (GNB3) (Fazakas et al, 2016), transcription factor Islet-1 gene (McNamara et al, 2014), troponin T (Friedrich et al, 2013), CYP2D6 polymorphism (Hofman et al, 2010), cardiac myosin binding protein-C mutations (Friedrich et al, 2013), renin-angiotensin-aldosterone system polymorphism (Sutter et al, 2013) etc. Indeed, it is well known that angiotensin-converting enzyme (ACE) I/D gene D allele was associated with higher overall mortality as compared with the I allele in HF patients and that the effect could be modified by ACE inhibitors' given (Kolder et al, 2012).…”