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Chronic Hypoxia Elevates Basal Tone in Neonatal Pulmonary Hypertension through PKC β and Reactive Oxygen Species Signaling
Author(s) -
Sheak Joshua R,
Jernigan Nikki L,
Walker Benjimen R,
Resta Thomas C
Publication year - 2016
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.30.1_supplement.774.16
Subject(s) - pulmonary hypertension , hypoxic pulmonary vasoconstriction , medicine , vasoconstriction , ventricle , right ventricular hypertrophy , vascular resistance , protein kinase c , pulmonary artery , lung , hypoxia (environmental) , reactive oxygen species , cardiology , endocrinology , blood pressure , chemistry , oxygen , signal transduction , biochemistry , organic chemistry
Vasoconstriction contributes to chronic hypoxia (CH)‐induced pulmonary hypertension in neonates. However, little is known regarding mechanisms of pulmonary vasoconstriction in this setting. PKC β is a conventional PKC isoform that contributes to a variety of cardiovascular disorders associated with oxidative stress. We hypothesized that neonatal CH mediates spontaneous pulmonary arterial tone through PKC β and reactive oxygen species (ROS) signaling. To test this hypothesis, we measured baseline pulmonary vascular resistance (PVR) in the presence and absence of PKC β inhibition with LY‐333,531 (10 nM) or ROS scavenging with the superoxide dismutase mimetic, TEMPOL (1 mM) using salt‐perfused lungs ( in situ ) from 2‐wk‐old control and CH (2 wk at 0.5 atm) rats. Microvascular pressure was determined by double occlusion technique, allowing calculation of arterial and venous resistances. As indices of pulmonary hypertension, we assessed peak right ventricular systolic pressure (RVSP) and right heart remodeling. Neonatal CH rats displayed elevated RVSP compared to controls (p<0.05), assessed by direct cardiac puncture in anesthetized animals. Furthermore, CH increased Fulton's index [right ventricle (RV)/left ventricle plus septum weight], indicative of RV hypertrophy. Lungs from animals in each group were pre‐treated with the NO synthase inhibitor, N ω ‐nitro‐L‐arginine (L‐NNA; 300 μM) or vehicle to evaluate the contribution of endogenous NO to PVR. The contribution of active tone to total and segmental baseline PVR was assessed by examining responses to exogenous NO (spermine NONOate, 100 μM). In the absence of L‐NNA, CH resulted in significant increases in total and arterial baseline vascular resistance (p<0.05), but had no effect on venous resistance. L‐NNA exaggerated CH‐dependent increases in total and arterial vascular resistance (p<0.05 vs. vehicle), but had no significant effect in control lungs. Consistent with our hypothesis, either PKC β inhibition or ROS scavenging reduced total and arterial baseline tone in lungs from CH neonates (p<0.05 vs. vehicle), while having no significant effect in controls. We conclude that PKCb and ROS contribute to spontaneous pulmonary arterial constriction in neonatal CH rats. Furthermore, this response to CH is limited by endogenous NO.