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Divergent Contractile and Structural Responses of the Murine Protein Kinase C-ε Null Pulmonary Circulation to Chronic Hypoxia* FREE TO VIEW

Cassana M. Littler, BA; C.A. Wehling; K.A. Fagan; R.O. Messing; E.C. Dempsey, FCCP
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*From the Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center and Denver Veterans Affairs Medical Center, Denver, CO; and the Department of Neurology, Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA.

Correspondence to: Cassana M. Littler, BA, CVP Research Laboratory, Box B133, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262; e-mail: cassana.littler@uchsc.edu

Chest. 2005;128(6_suppl):620S-621S. doi:10.1378/chest.128.6_suppl.620S
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Protein kinase C (PKC)-ε regulates myocardial and lung vascular responses to ischemia and acute hypoxia (Hx) by discrete tissue-specific mechanisms. The activation of PKC-ε protects against acute ischemic injury in the heart, while in the lung we have shown that the loss of PKC-ε limits the magnitude of acute hypoxic pulmonary vasoconstriction. Adaptation of the lung circulation to chronic Hx is a more complex process than these acute responses. The pattern of lung vascular responses to chronic Hx may or may not be predicted by acute hypoxic pulmonary vasoconstriction. Therefore, we hypothesized that the loss of PKC-ε would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic Hx. Adult PKC-ε wild-type (+/+) mice and null (–/–) mice were exposed to normoxia (5,200 feet) or Hx (18,000 feet) for 5 weeks.

Interestingly, PKC-ε −/− mice had a much greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to Hx than +/+ mice (n = 9 to 13 mice per group; p < 0.05). Despite the increased pulmonary artery pressure and RV hypertrophy, PKC-ε null mice showed no further pulmonary vascular remodeling compared to controls. The acute inhalation of nitric oxide reversed the increased vascular tone in chronically hypoxic null mice, implying that the exaggerated pulmonary hypertension seen here could be due to a relative deficiency in endothelial nitric oxide synthase (eNOS) expression/activity. Baseline eNOS protein expression was similar in PKC-ε +/+ and −/− lungs. The expected Hx-induced increase in lung eNOS expression was attenuated in PKC-ε null mice.

These results demonstrate that the contractile and structural responses of the murine lung circulation to chronic Hx can be uncoupled from one another, and a relative deficiency in Hx-induced eNOS expression/activity probably contributes to increased vascular tone in the chronically hypoxic PKC-ε null mouse. The loss of PKC-ε provides relative protection from exaggerated pulmonary vascular remodeling, but not RV remodeling, in response to chronic Hx. Collectively, these findings suggest that PKC-ε is an important determinant of susceptibility to chronic hypoxic pulmonary hypertension.

Abbreviations: eNOS = endothelial nitric oxide synthase; Hx = hypoxia; PKC = protein kinase C




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