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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/L1083    most recent 00472.2004v2 00472.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Littler, C. M. Articles by Dempsey, E. C. Search for Related Content PubMed PubMed Citation Articles by Littler, C. M. Articles by Dempsey, E. C.

Divergent contractile and structural responses of the murine PKC- null pulmonary circulation to chronic hypoxia

¹Cardiovascular Pulmonary Research Laboratory and ²Department of Pathology, University of Colorado Health Sciences Center; and ³Denver Veterans Administration Medical Center, Denver, Colorado; and ⁴Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, California

Submitted 22 December 2004 ; accepted in final form 25 July 2005

Loss of PKC- limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC- would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic hypoxia (Hx). However, the pattern of lung vascular responses to chronic Hx may or may not be predicted by the acute HPV response. Adult PKC- wild-type (PKC-^+/+), heterozygous null, and homozygous null (PKC-^–/–) mice were exposed to normoxia or Hx for 5 wk. PKC-^–/– mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-^+/+ mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-^+/+ mice) in both the proximal and distal PKC-^–/– pulmonary vasculature. The contribution of increased vascular tone to this pulmonary hypertension (PHTN) was assessed by measuring the acute vasodilator response to nitric oxide (NO). Acute inhalation of NO reversed the increased PA pressure in hypoxic PKC-^–/– mice, implying that the exaggerated PHTN may be due to a relative deficiency in nitric oxide synthase (NOS). Despite the higher PA pressure, chronic Hx stimulated less of an increase in lung endothelial (e) and inducible (i) NOS expression in PKC-^–/– than PKC-^+/+ mice. In contrast, expression of nNOS in PKC-^+/+ mice decreased in response to chronic Hx, while lung levels in PKC-^–/– mice remained unchanged. In summary, loss of PKC- results in increased vascular tone, but not pulmonary vascular remodeling in response to chronic Hx. Blunting of Hx-induced eNOS and iNOS expression may contribute to the increased vascular tone. PKC- appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform.

mouse; knockout; pulmonary hypertension; endothelial; inducible and neuronal nitric oxide synthase; vascular remodeling; protein kinase C epsilon

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