Target Nuclear Factor Erythroid 2-Related Factor 2 in Pulmonary Hypertension: Molecular Insight into Application

Table 1

Research of phytochemical Nrf2 activator in pulmonary hypertension.

Phytochemical	Dose	Administration route	Model	Mechanism	Benefit	Reference
Resveratrol	50 mg/l	Oral	Spontaneously hypertensive rats (SHR)	Restored Nrf2 and GST activity	Mitigated renal inflammation; Reduced oxidative stress; Attenuated the progression of hypertension in SHR.	[89]
SFN	0.5 mg/kg for 5 days	Subcutaneous injection	Su5416 and 10% hypoxia exposure for 4 weeks	Nrf2/NQO1 upregulation	Protected mice from developing and RV dysfunction	[93, 94]
DMF	90 mg/kg	Intraperitoneal	Chronic hypoxia and hypoxia/SU5416 mouse models	Inhibited proinflammatory NFκB, STAT3 and cJUN signaling; Promoted βTRCP-dependent proteasomal degradation of fibrogenic mediators β-catenin, TAZ and Sp1	Reversed hemodynamic changes; Reduced inflammation, oxidative damage, and fibrosis; Ameliorated vascular muscularization	[95]
DMF	Week 1: 120 mg qd; Weeks 2-3: 120 mg bid; Weeks 3-7: 120 mg qam; 240 mg qpm; Weeks 8-24: 240 mg twice	Oral	PAH patients associated with systemic sclerosis	—	Withdrawn after serious adverse event; Nonsignificantly reduced decline in 6MWD (7.07% vs. -14.97%) from baseline to week 24 compared to placebo-treated subjects	[97]
PA	5 mg/kg per day	—	Hypoxia-induced PH model	Activated Nrf2-Keap1-ARE signaling pathway	Significantly reversed right ventricular hypertrophy and PVR; Inhibited proliferation and promoted apoptosis in hypoxia-induced PASMCs	[101]
SAA	0.3, 1, and 3 mg/kg	Gavage	MCT-induced PAH model	Stimulated Nrf2 translocation and subsequent HO-1 upregulation	Attenuated EndMT, inhibited ROS formation.; Improved vascular function and inhibited inflammation	[107]
Simvastatin	0.1% and 0.5% w/v	Inhalation	Shunt lamb model of PH	Nrf2 activation and RhoA/Rho kinase inhibition	Restored endothelial function and reduced PVR	[108]
ANDRO	1 mg/kg/day	Intraperitoneal	Chronic hypoxia- and Sugen/hypoxia-induced PH	Blocked ROS generation by suppressing NOX activation and augmenting Nrf2 expression.	Decreased PVR, mPAP, and right ventricular hypertrophy; Reduced cell viability, proliferation and migration; Increased PASMC apoptosis	[110]
BB	50, 100, and 200 mg/kg	Gavage	MCT-induced PH model	Restored Nrf2 expression in the lungs	Increased the E/A ratio across the tricuspid valve and tricuspid annular phase systolic excursion; Decreased mPAP	[111]
CODO-NO	2.1 μg/kg	Nose-only exposure system	MCT-induced pH model	Inhibited overproliferation of perivascular cells; Diminished macrophage infiltration and oxidative stress by inactivation of NOX4.	Exhibited inhibition of pulmonary vasodilation and vascular remodeling; Reduced cardiac hypertrophy and fibrosis	[116]
Ligustrazine	1% in methanol	Inhalation	MCT induced PH model	Nrf2/ARE activation and a Rho/ROCK inhibition.	Significantly decreased RVSP	[118]
Oxymatrine	50 mg/kg/day	Oral	MCT and hypoxia induced PH model	Significantly upregulated Nrf2 and downstream SOD1, HO-1 expression; Downregulated hydroperoxide levels	Attenuated RVSP and PVR	[119]
Oltipraz	50 mg/kg/d	Gavage	Hypoxia induced PH	Nrf2 activation	Ameliorated right ventricular hypertrophy	[85]