Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr -/- mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr -/- mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.
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PMID:Long noncoding RNA SNHG12 integrates a DNA-PK-mediated DNA damage response and vascular senescence. 3207 42

A century ago a fat-soluble vitamin from leafy vegetables, later named vitamin E, was discovered to enhance fertility in animals. Vitamin E consists of 8 isomers of tocopherols and tocotrienols, each containing chromanol groups that confer antioxidant properties and differ only in the 15-carbon saturated phytyl poly-isoprenoid side chain of tocopherols and the 15-carbon unsaturated farnesyl poly-isoprenoid side chain of tocotrienols. Although tocotrienol was first isolated from rubber plants in 1964, its importance in multiple disease processes was not recognized until two decades later, when the cholesterol-lowering and anti-cancer effects were first reported. Tocotrienol (T3) protects against radiation injury and mitochondrial dysfunction by preventing opening of the mitochondrial permeability transition pore, thereby inhibiting loss of the active site for oxidative phosphorylation, thioretinaco ozonide oxygen ATP, from mitochondria by complex formation with the active site, TR2CoO3O2NAD+H2PO4 -T3. The preventive effects of tocotrienol on vascular disease, cancer, neurodegeneration and aging are attributed to its effects on cellular apoptosis and senescence. Geranylgeraniol is an important intermediate in the biosynthesis of cholesterol, and cholesterol auxotrophy of lymphoma cell lines and primary tumors is attributed to loss of squalene monooxygenase and accumulation of intracellular squalene. Geranylgeraniol and tocotrienol have synergistic inhibitory effects on growth and HMG CoA reductase activity, accompanied by reduction of membrane KRAS protein of cultured human prostate carcinoma cells. Since cholesterol inhibits opening of the mPTP pore of mitochondria, inhibition of cholesterol biosynthesis by these effects of tocotrienol and geranylgeraniol produces increased mitochondrial dysfunction and apoptosis from loss of the active site of oxidative phosphorylation from mitochondria.
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PMID:Chemical Pathology of Homocysteine VIII. Effects of Tocotrienol, Geranylgeraniol, and Squalene on Thioretinaco Ozonide, Mitochondrial Permeability, and Oxidative Phosphorylation in Arteriosclerosis, Cancer, Neurodegeneration and Aging. 3306 2


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