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DNA‐PK Is Activated in Human Atherosclerotic Plaques And Its Partial Inhibition by Gene Heterozygosity Reduces Atherogenesis in Mouse Model of The Disease
Author(s) -
Ghonim Mohamed A.,
Pyakurel Kusma,
Luu Hanh,
Dean Matthew,
Bazan Hernan,
Boulares Hamid
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.570.2
Subject(s) - inflammation , loss of heterozygosity , gene , cancer research , dna damage , biology , dna repair , dna , immunology , medicine , pathology , allele , genetics
Atherosclerosis is a chronic inflammatory condition with serious implications including coronary heart disease, cerebrovascular and thromboembolic disorders. Rupture of plaques, the subsequent formation of thrombi, and the consequent occlusion of arteries are the most important events in the onset of cardiovascular complications associated with atherosclerosis. The ultimate clinical goal to prevent plaque rupture and thrombosis is the stabilization and potential regression of vulnerable plaques. DNA‐PK is composed of a 450‐kDa catalytic subunit (DNA‐PKcs) and two DNA‐binding subunits (Ku70/Ku80). Although DNA‐PK is critical for repairing DSBs through non‐homologous end joining, only less than 1% is needed to achieve such function. We have recently reported that partial inhibition of DNA‐PK pharmacologically by NU7441 or genetically by gene heterozygosity reduces asthma‐like traits in 2 animal models of the disease in part by blocking lung VCAM‐1 expression, production of Th2 cytokines through down regulating the expression of several inflammatory genes. Since persistent inflammation is critical for plaque instability and rupture, we sought to examine the role of DNA‐PK in human atherogenesis and determine whether its activation correlates with factors of inflammation and/or markers of DNA damage/repair and to investigate whether inhibition of the enzyme promotes plaque regression in a mouse model of atherosclerosis. We report that DNA‐PKcs is activated in inflammatory as well as structural cells within human atherosclerotic plaques of carotid arteries. Reduction of DNA‐PKcs by gene heterozygosity, which reduces expression and activity of the enzyme by ~50%, promoted a significant reduction of the atherosclerotic burden in high fat diet‐fed (HFD) ApoE −/− mice. Such protective action was accompanied by a significant reduction in LDL levels and an increase in HDL. These effects were achieved without interference or activation of the DNA damage/repair pathways or the development of severe combined immunodeficiency (SCID) syndrome. Overall, our results support the notion that DNA‐PK is a key player in atherogenesis and that it may constitute a novel therapeutic target for the modulation of the disease. Support or Funding Information NIH/COBRE 1P30GM106392‐01: COBRE Phase III Transitional Center Grant‐ Mentoring in Cardiovascular Biology This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .