Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension is associated with a decreased antioxidant capacity. However, neither the contribution of reactive oxygen species to pulmonary vasoconstrictor sensitivity, nor the therapeutic efficacy of antioxidant strategies in this setting are known. We hypothesized that reactive oxygen species play a central role in mediating both vasoconstrictor and arterial remodeling components of severe pulmonary arterial hypertension. We examined the effect of the chemical antioxidant, TEMPOL, on right ventricular systolic pressure, vascular remodeling, and enhanced vasoconstrictor reactivity in both chronic hypoxia and hypoxia/SU5416 rat models of pulmonary hypertension. SU5416 is a vascular endothelial growth factor receptor antagonist and the combination of chronic hypoxia/SU5416 produces a model of severe pulmonary arterial hypertension with vascular plexiform lesions/fibrosis that is not present with chronic hypoxia alone. The major findings from this study are: 1) compared to hypoxia alone, hypoxia/SU5416 exposure caused more severe pulmonary hypertension, right ventricular hypertrophy, adventitial lesion formation, and greater vasoconstrictor sensitivity through a superoxide and Rho kinase-dependent Ca2+ sensitization mechanism. 2) Chronic hypoxia increased medial muscularization and superoxide levels, however there was no effect of SU5416 to augment these responses. 3) Treatment with TEMPOL decreased right ventricular systolic pressure in both hypoxia and hypoxia/SU5416 groups. 4) This effect of TEMPOL was associated with normalization of vasoconstrictor responses, but not arterial remodeling. Rather, medial hypertrophy and adventitial fibrotic lesion formation were more pronounced following chronic TEMPOL treatment in hypoxia/SU5416 rats. Our findings support a major role for reactive oxygen species in mediating enhanced vasoconstrictor reactivity and pulmonary hypertension in both chronic hypoxia and hypoxia/SU5416 rat models, despite a paradoxical effect of antioxidant therapy to exacerbate arterial remodeling in animals with severe pulmonary arterial hypertension in the hypoxia/SU5416 model.

Senescence Marker Protein 30 Deficiency Exacerbates Pulmonary Hypertension in Hypoxia-Exposed Mice

“…[1][2][3][4] Pulmonary vasoconstriction is induced by the reduction of vasodilators such as nitric oxide (NO) and/or the production of vasoconstrictors such as endothelin-1 and oxidative stress. [5][6][7][8] In addition, it is known that resistance to apoptosis mediated by bone morphogenic protein (BMP) signals or transforming growth factor (TGF)-β signals is involved in the excessive proliferation of pulmonary artery endothelial cells and smooth muscle cells. [9][10][11] However, the detailed mechanisms remain unclear.…”

AGE–RAGE Stress in the Pathophysiology of Pulmonary Hypertension and its Treatment

“…As mentioned earlier, 72,73 ROS plays a major role in the development of PH. Considering that antioxidants may be an option for the treatment of PH.…”

“…72 ROS plays a role in mediating vasoconstrictor reactivity and pulmonary hypertension in both chronic hypoxia and hypoxia/SU5416 rat model. 73 AGE-RAGE-induced generation of ROS increases the pulmonary arterial pressure directly and through hypertrophy of pulmonary artery. The above data suggest that AGE and its interaction with RAGE play a crucial role in pathogenesis of PH.…”

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

“…The dose of NP used in this study was 100 times lower than the concentration of the antioxidant, TEMPOL, normally used in treating PAH, and it did not affect the redox homeostasis of the cellular environment. It was also recently reported that TEMPOL treatment was not effective in preventing pulmonary arterial remodeling and, in fact, increased the severity of PAH [14].…”