Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near
GPR78
, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
Nitric oxide (NO) synthesis in endothelial cells is impaired in diabetes. We previously showed that impaired NO synthesis in the spontaneously diabetic BB (BBd) rat is due to decreased levels of tetrahydrobiopterin (BH4), secondary to decreased expression of GTP cyclohydrolase I (GTPCH). The aim of this study was to utilize adenoviral GTPCH gene transfer to reverse BH4 deficiency and repair the ability of endothelial cells to produce NO. GTPCH gene transfer increased BH4 levels in BBd endothelial cells from 0.17 +/- 0.02 (mean +/-SE) to 73.37 +/- 14.42 pmol/million cells and NO production from 0.77 +/- 0.07 to 18.74 +/- 5.52 nmol/24 h/million cells. To demonstrate a functional effect of increasing BH4 concentrations in tissues, we transferred GTPCH into aortic rings from BBd and Zucker diabetic fatty (ZDF) rats, models of human type I and type II diabetes, respectively. GTPCH gene transfer led to a dose-dependent increase in acetylcholine-induced vasorelaxation, preventable by inhibiting NO synthase. Maximal relaxation of virus-treated rings (10(10) virus particles/ml) to acetylcholine was significantly higher than sham-treated rings (BBd 64% vs. 37%, P<0.005; ZDF 80% vs. 44%, P<0.05). This study demonstrates that GTPCH gene transfer can reverse BH4 deficiency in both type I and type II diabetes and provides an experimental basis for using gene therapy to treat cardiovascular complications in diabetic patients.
The concentration of free epinephrine and norepinephrine in plasma and 24-hr urine samples, collected from members of the Dutch Monte Rosa expedition (July 1963) was investigated during 17 days at various altitudes up to 4,560 m. The results indicate that the levels of both plasma and urine catecholamines were elevated during the expedition, the plasma levels reaching a maximum towards the end of the 12 days sojourn at 4,560 m. In general there was a twofold increase in total catecholamine concentration in the samples collected at high altitude as compared to control values at sea level. This difference was due to a significant increase in the norepinephrine concentration; there was little change in epinephrine level. epinephrine and norepinephrine; sympathoadrenal activity Submitted on September 2, 1964
Among chicken strains, broilers are prone to pulmonary hypertension, whereas Leghorns are not. Relaxations to endothelium-dependent (ACh, A23187) and endothelium-independent [sodium nitroprusside (SNP), papaverine (PPV)] vasodilators were compared in preconstricted pulmonary artery (PA) rings from these chicken strains. ACh (10−7, 10−6, and 10−5 M)- and A23187 (10−6 and 10−5.5 M)-induced relaxations were smaller ( P < 0.05) in broilers than Leghorns. N G-nitro-l-arginine methyl ester (10−3.5 M) caused similar reductions in ACh-induced relaxations in both strains.l-Arginine (10−4 M) enhanced ACh-induced relaxations more in broilers than Leghorns. Relaxations to 10−10–10−6M SNP did not differ between strains, but were greater ( P < 0.05) in broilers than Leghorns at higher concentrations (10−5 and 10−4 M). PPV (10−4 M)- and SNP (10−4 M)-induced maximal relaxations were greater in broilers than in Leghorns (176.2 ± 14.7 vs. 120.9 ± 14.7% and 201.3 ± 7.8 vs. 171.2 ± 10.7%, respectively, P < 0.05). Broiler PA rings appear to have increased intrinsic tone and reduced endothelium-derived nitric oxide activity, both of which may contribute to the susceptibility of broiler chickens to pulmonary hypertension.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.