Histone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide Synthase

Abstract

Rationale: Low-dose acetylsalicylic acid (aspirin) is widely used in the treatment and prevention of vascular atherothrombosis. Cardiovascular doses of aspirin also reduce systemic blood pressure and improve endotheliumdependent vasorelaxation in patients with atherosclerosis or risk factors for atherosclerosis. Aspirin can acetylate proteins, other than its pharmacological target cyclooxygenase, at lysine residues. The role of lysine acetylation in mediating the effects of low-dose aspirin on the endothelium is not known. Objective:To determine the role of lysine acetylation of endothelial nitric oxide synthase (eNOS) in the regulation of endothelial NO production by low-dose aspirin and to examine whether the lysine deacetylase histone deacetylase (HDAC)3 antagonizes the effect of low-dose aspirin on endothelial NO production by reversing acetylation of functionally critical eNOS lysine residues. Methods and Results: Low concentrations of aspirin induce lysine acetylation of eNOS, stimulating eNOSenzymatic activity and endothelial NO production in a cyclooxygenase-1-independent fashion. Low-dose aspirin in vivo also increases bioavailable vascular NO in an eNOS-dependent and cyclooxygenase-1-independent manner. Low-dose aspirin promotes the binding of eNOS to calmodulin. Lysine 609 in the calmodulin autoinhibitory domain of bovine eNOS mediates aspirin-stimulated binding of eNOS to calmodulin and eNOS-derived NO production. HDAC3 inhibits aspirin-stimulated (1) lysine acetylation of eNOS, (2) eNOS enzymatic activity, (3) eNOS-derived NO, and (4) binding of eNOS to calmodulin. Conversely, downregulation of HDAC3 promotes lysine acetylation of eNOS and endothelial NO generation. Key Words: aspirin Ⅲ endothelial NOS Ⅲ HDAC3 Ⅲ lysine acetylation Ⅲ calmodulin L ow-dose aspirin (81 to 325 mg/d) is a very useful tool in the armamentarium for the treatment of acute coronary syndromes, as well as for the secondary prevention of myocardial infarctions and stroke in high-risk patients. 1 The antithrombotic effects of low-dose aspirin are principally attributed to acetylation of a serine residue in platelet cyclooxygenase (COX)-1, irreversibly inhibiting COX-1 in platelets, and limiting platelet aggregation because of prostanoids produced by COX-1. 2 In addition to preventing thrombosis, low-dose aspirin also improves vasomotor function mediated by the endothelium in humans 3,4 and in animal models of endothelial dysfunction. 5 Although low-dose aspirin is not commonly used in the treatment of hypertension, it is efficacious, when given at bedtime, for reduction of blood pressure in individuals with mild hypertension 6,7 or prehypertension. 8 Suppression of vasoconstricting prostanoids produced by COX-1 could be one mechanism by which low-dose aspirin improves endothelial function and reduces mildly and bor- Low-dose aspirin increases NO produced by blood vessels, 9 but the mechanism responsible for this effect is not fully understood. Cardiovascular doses of aspirin increase nitric oxide synthase (NOS) enzymatic activit...

Non-steroidal anti-inflammatory drugs attenuate the vascular responses in aging metabolic syndrome rats

“…Some effects of NSAIDs on the vasculature have been reported, but the mechanisms responsible for these effects are not fully understood [26] . In the older human population, people frequently have multiple problems.…”

“…Jung et al [26] have reported that a low-dose of aspirin increases the NO produced by blood vessels, but the mechanism responsible for this effect is not fully understood. Aspirin use for cardiovascular diseases increases NOS enzymatic activity in endothelial cell homogenates and platelets, and aspirin at high concentrations acetylates eNOS serine residues.…”

“…Although COX-2 is induced as part of the inflammatory response, COX-2 has recently been reported to be constitutively expressed in the vascular endothelium [20,[23][24][25] . COX-2 is increased in blood vessels of individuals with cardiovascular risk factors [26] . Recently, the prostanoid production from constitutively expressed COX-2 has been shown to be involved in modulating vascular responses [27][28][29] .…”

Galectin-9 Protein Expression in Endothelial Cells Is Positively Regulated by Histone Deacetylase 3

“…Disruption of the HDAC3 gene in mouse germ line causes early embryonic lethality (21). In endothelial cells, HDAC3 can regulate agonist-induced tissue factor expression (22), eNOS expression (23) and activity (24) as well as VCAM-1 expression (25). In our laboratory, we have shown that HDAC3 is essential for stem/progenitor cell differentiation toward endothelial lineage (26,27) and plays a prosurvival role in mature endothelial cells (28).…”

Aging in blood vessels. Medicinal agents FOR systemic arterial hypertension in the elderly

“…Although the mechanism by which blood pressure rises with NSAIDs is not known, it is probably through inhibition of prostaglandin synthesis (Egan and FitzGerald, 2006). Jung et al (2010) have reported that a low-dose of aspirin increases NO produced by blood vessels, but the mechanism responsible for this effect is not fully understood. Doses of aspirin employed for cardiovascular diseases increase NOS enzymatic activity in endothelial cell homogenates and in platelets, and aspirin at high concentrations acetylates endothelial eNOS serine residues.…”