Endothelial dysfunction in cirrhosis: Role of inflammation and oxidative stress

Table 1 Factors affecting endothelial dysfunction in cirrhosis

Marker	Endothelial dysfunction	Ref.
Inflammatory marker
TNF-α	Inhibition of NO synthesis	[47,75,78,84,99,104]
NFκB	Increase of ADMA
TLR	Increase of Caveolin-1
Ang II	Reduction of eNOS activity
	Inhibition of DDAH enzyme
	Upregulation of iNOS
	Increase of superoxide production
	Reduction of antioxidant capacity
Oxidative marker
4-HNE	Reduction of DDAH enzyme activity	[42,78,104]
NADPH	Decrease of NO bioavailability
	Increase of ADMA levels
	Increase of ROS generation
Cyclooxygenase -derived prostanoids
TXA2	Reduction of intrahepatic nitrate/nitrite	[110-112]
PGI2	Upregulation of iNOS expression
	Increase of intrahepatic resistance
Other marker
ET-1	Increase of inflammation	[122,130,138,139, 145]
LOX-1	Stimulation of ROS generation
PARs
Adiponectin
Palmitic acid

TNF-α: Tumor necrosis factor-α; NFκB; Nuclear factor kappa B; TLR: Toll like receptor; Ang II: Angiotensin II; NO: Nitric oxide; ADMA: Asymmetric dimethylarginine; eNOS: Endothelial nitric oxide synthase; DDAH: Dimethyl arginine diaminohydrolase; iNOS: Inducible nitric oxide synthase; 4-HNE: 4-hydroxy-2-nonenal; NADPH; Nicotinamide adenine dinucleotide phosphate-oxidase; ROS: Reactive oxygen species; TXA2: Thromboxane A2; PGI2: Prostaglandin I2; ET-1: Endothelin -1; LOX-1: Lectin-like oxidized low-density lipoprotein receptor-1; PARs: Protease activated receptors.

Table 2 Classic and novel therapeutic strategies directing to improvement of endothelial dysfunction in cirrhosis

Therapeuticagent	Endothelial function	Ref.
Anti- inflammatory agents	Increase of NO bioavailability	[25,42,75,111]
	Reduction of ADMA
	Upregulation of eNOS activity
	Decrease of Inflammation
Vitamins	Improvement of eNOS activity	[159,160,162]
	Increase of NO bioavailability
	Scavenging of ROS generation
	Antioxidant function
Flavonoids	Increase of NO bioavailability	[15,166,168]
	Prevention of oxidative stress
	Improvement of antioxidant enzymes
Nuclear receptors	Increase of NO bioavailability	[33,50,187]
	Improvement of DDAH
	Reduction of ADMA
	Amelioration of hepatic vascular tone
Ammonia lowering agents	Detoxification of ammonia levels	[27,189,190,192,201]
	Increase of NO bioavailability
	Reduction of ADMA
	Upregulation DDAH expression
Statins	Decrease of total cholesterol	[147,170,172,202,203]
	Improvement of Akt-dependent eNOS phosphorylation
	Promoting NO biosynthesis
	Reduction of Ox-LDL
	Attenuation of inflammatory indices
Beta blockers	Amelioration of oxidative stress	[194,196]
	Attenuation of Inflammation
	Restoration of antioxidant enzymes
Angiotensin- receptor antagonists	Increase of NO	[200,204]
	Decrease of Ang-II mediated inflammation
	Decrease of TIMP-1, MMP-2 mediated fibrosis

NO: Nitric oxide; ADMA: Asymmetric dimethylarginine; eNOS: Endothelial nitric oxide synthase; DDAH: Dimethyl arginine diaminohydrolase; Ox-LDL: Oxidized low-density lipoprotein; Ang II: Angiotensin II; TIMP-1: Tissue inhibitor of metalloproteinase 1; MMP-2: Matrix metalloproteinase-2.