Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Endothelial Nitric Oxide Synthase (eNOS) S1176 phosphorylation status governs atherosclerotic lesion formation ObjectiveWe have previously demonstrated the in vivo importance of the Akt-eNOS substrate-kinase 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 & ResultsWe 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.

ConclusionsBy 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.
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The categories of this paper are: toxicology
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The categories of this paper are: evolutionary
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The categories of this paper are: biochemistry
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The categories of this paper are: education
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The categories of this paper are: animal
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The categories of this paper are: developmental
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The categories of this paper are: molecular
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The categories of this paper are: bioengineering
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The categories of this paper are: bioinformatics
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The categories of this paper are: plant
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The categories of this paper are: ecology
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The categories of this paper are: epidemiology
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The categories of this paper are: pharmacology
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The categories of this paper are: synthetic
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The categories of this paper are: microbiology
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The categories of this paper are: immunology