Table 1.

Animal models of flow mediated EC senescence and AS formation.

Type of DNA damage response	DNA damage response factors	Functions	Animal models	DDR and atherosclerosis in EC	Ref
Nucleotide Excision Repair (NER)	NER-DNA crosslink repair (XLR) endonuclease ERCC1	Involved in the repair of nucleotide excision repair	Ercc1d/− mice, having mutation in one allele of the enzyme ERCC1	The EC from the mutant mice exhibited higher senescence compared to the WT mice. In addition, mutant mice developed age dependent vascular dysfunction.	[55]
Spindle assembly checkpoint protein	BubR1	Detect the correct microtubule-kinetochore attachment and segregation of chromatids during mitosis	Hypomorphic BubR1 mutant (BubR1H/H) Mice expressing mutant BubR1	Increased production of superoxide anions, aging-associated phenotypes, EC dependent relaxation is lost, accelerated cardio vascular aging	[56,57]
Telomerase and Shelterin complex	TERC, TERT	TERT produces telomeric repeats using the template provided by TERC	TERC−/− and TERT−/− mice	Telomerase deficient mice exhibited an increased activity of nicotinamide adenine dinucleotide phosphate oxidase, and high levels of reactive oxygen species, leading to increased hypertension and vascular dysfunction	[58]
	TERF2IP	A member of the shelterin complex of the mammalian TLs binds to both telomeric and nontelomeric chromatins and in the protection of TLs	TERF2IP−/− mice	Conferred protection against d-flow–induced EC senescence, apoptosis, and AS plaque formation	[59]
Base Excision Repair of Oxidative DNA Damage	Base excision repair enzyme 8oxoG DNA glycosylase I (OGG1)	Involved in the BER mechanism for the repairing of 8-Oxoguanine (8oxoG), which is one of the most abundant oxidative DNA damage	OGG1−/− mice in vascular smooth muscle cells (VSMC)	Mice exhibited oxidative stress, DNA strand breaks, pro-inflammatory pathways and extensive AS formation	[60]
	Apurinic/Apyrmidinic Endonuclease-1 (APE1)/redox factor-1 (ref-1)	Essential for BER pathway, DNA repair and governs the reductive activation of many redox-sensitive transcription factors	APE1/ref-1+/− mice	The transgenic mice manifested reduced vascular NO level, dysregulated EC dependent vascular tone and developed systemic hyper tension and vascular complications	[61]
Sensor of DNA damage	Sirtuin 1 (SIRT1)	NAD + dependent acetylation of proteins and involved in the rescue of DNA damage induced apoptosis	ApoE-null mice with SIRT1 over expression	SIRT1 over expressing mice showed protection against high fat-induced impairment in endothelium-dependent vasorelaxation had lesser AS formation than the control ApoE−/− mice	[62]
	PARP-1	ADP-ribosylating enzyme activated upon ssDNA damage DSB. PARP-1 cleaves NAD + into nicotinamide and adds polymers of ADP-ribose to glutamic acid residues substrates	Diabetic mice with PARP1 KO db−/db−PARP-1−/−	The inhibition of PARP-1 activity by pharmaceutical and in db−/db− mice, significantly improved vascular function and tone. NF-κB is shown to regulate vascular function through PARP-1	[63]
Transducer proteins of DDR pathway	ATM	Transduces the DNA damage signal to the downstream effectors	ATM ± ApoE−/− mice	Developed accelerated AS	[64]
	p53	Regulation of cell cycle and DDR activator	High fat diet in LDLR−/− mice	Disturbed Flow sites expressed high levels of SAβG activity and p53 expression and DF induced senescence is mediated through p53-p21 pathway	[65]
	p21	Involved in G1/S checkpoint in the cell cycle	p21 −/− mice	Accelerated AS formation in high fat diet induced atherosclerosis in knock out mice compared to the WT	[66]