Characterization of the rat basilar artery in vitro

Summary Segments of the rat basilar artery were examined in vitro for their mechanical responsiveness to a variety of vasoactive substances. Serotonin was the most potent agonist while norepinephrine elicited a dose-dependent relaxation. The findings lend support to the concept that there exists a marked heterogeneity amongst species in cerebrovascular responsiveness.This work was supported by grants from the National Institutes of Health (NIHLBI-06080, 18575).     

Vascular reactivity in hypertension: Altered effect of ouabain

Summary Ouabain inhibits the relaxing effect of Ca²⁺ (but not of Mn²⁺) on contractile responses in tail artery strips isolated from spontaneously hypertensive and normotensive rats. The magnitude of ouabain inhibition was greater in vascular strips from hypertensive rats suggesting a significant difference in basic membrane function in hypertensive vascular smooth muscle.These studies were supported by National Heart, Lung, and Blood Institute grants HL-03765 and HL-18575-02-03. R.C. Webb is a Postdoctoral Research Fellow of the Michigan Heart Association.     

SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin

The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.