Endothelial Nitric Oxide Synthase (eNOS) S1176 phosphorylation status governs atherosclerotic lesion formation

Objective: We have previously demonstrated the in vivo importance of the Akt-eNOS substratekinase relationship, as defective postnatal angiogenesis characteristic of global Akt1-null mice is rescued when bred to gain-of-function eNOS S1176D mutant mice. While multiple studies support the cardioprotective role of endothelial NO generation, the causal role of Akt1-dependent eNOS S1176 phosphorylation during atherosclerotic plaque formation is not yet clear. Approach & Results: We herein bred congenic loss-of-function eNOS S1176A and gain-of function eNOS S1176D mutant mice to the proatherogenic Akt1-/-; ApoE-/- double knockout mice to definitively test the importance of Akt-mediated eNOS S1176 phosphorylation during atherogenesis. We find that a single amino acid substitution at the eNOS S1176 phosphorylation site yields divergent effects on atherosclerotic plaque formation, as an eNOS phospho-mimic aspartate (D) substitution at S1176 leads to decreased indices of atherosclerosis, even when on a proatherogenic Akt1 global deletion background. Conversely, mice harboring an unphosphorylatable mutation to alanine (S1176A) result in increased lipid deposition and cellular apoptosis, phenocopying the physiological consequence of eNOS deletion and/or impaired enzyme function. Furthermore, gene expression analyses of whole aortas indicate a combinatorial detriment from NO deficiency and Western Diet challenge, as loss-of-function eNOS SA mice on a high-fat and high-cholesterol diet present a unique expression pattern indicative of augmented T-cell activity when compared to eNOS S1176D mice. Conclusions: By using genetic epistasis approaches, we conclusively demonstrate that Akt mediated eNOS S1176 phosphorylation and subsequent activation remains to be the most physiologically relevant method of NO production to promote cardioprotective effects.

The scent of atherosclerosis

Vascular macrophages sense an odorant to induce atherosclerotic plaque formation

Analysis of Serum Cholesterol, Statins and Atherosclerotic Plaque in Ruptured and Unruptured Intracranial Aneurysm

Introduction Intracranial aneurysm (IA) is a major healthcare concern. The use of statin to reduce serum cholesterol has shown evidence to reduce cardiovascular risk in various diseases, but the impact on IA has not been described. This study aims to determine whether statin use, and serum cholesterol levels interfere with outcomes after IA event. Methods A cohort of patients with IA was analyzed. Patients social and demographics data were collected. Modified Rankin scale (mRS) score after 6 months of follow-up was the endpoint. The data regarding statins use, presence or not of atherosclerotic plaque in radiological images and serum cholesterol of 35 patients were included in our study. Linear regression models were used to determine the influence of those 6 variables in the clinical outcome. Results The prevalence of atherosclerotic plaque, high cholesterol and use of statins was 34.3%, 48.5%, and 14.2%, respectively. Statins and serum cholesterol did not impact the overall outcome, measured by mRS after 6 months (p > 0.05), but did show different tendencies when separated by IA rupture status. Serum cholesterol shows an important association with rupture of aneurysm (p = 0.0382). High cholesterol and use of statins show a tendency for worse outcome with ruptured aneurysm, and the opposite is true for unruptured aneurysm. The presence of atherosclerotic plaques was not related with worse outcomes. Conclusions Multiple and opposite mechanisms might be involved in the pathophysiology of IA. Ruptured aneurysms are associated with higher levels of serum cholesterol. Serum cholesterol and statins use were not correlated with worse outcomes, but further studies are important to clarify these relationships.