Divergent contractile and structural responses of the murine PKC-epsilon null pulmonary circulation to chronic hypoxia.
Loss of PKC-epsilon limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC-epsilon 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-epsilon wild-type (PKC-epsilon(+/+)), heterozygous null, and homozygous null (PKC-epsilon(-/-)) mice were exposed to normoxia or Hx for 5 wk. PKC-epsilon(-/-) mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-epsilon(+/+) mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-epsilon(+/+) mice) in both the proximal and distal PKC-epsilon(-/-) 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-epsilon(-/-) 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-epsilon(-/-) than PKC-epsilon(+/+) mice. In contrast, expression of nNOS in PKC-epsilon(+/+) mice decreased in response to chronic Hx, while lung levels in PKC-epsilon(-/-) mice remained unchanged. In summary, loss of PKC-epsilon 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-epsilon appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform.
Littler
C M
CM
Cardiovascular Pulmonary Research Laboratory, B-133, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262, USA. Cassana.Littler@uchsc.edu
Wehling
C A
CA
Wick
M J
MJ
Fagan
K A
KA
Cool
C D
CD
Messing
R O
RO
Dempsey
E C
EC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000860:Hypoxia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D051744:Protein Kinase C-epsilon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D051744:Protein Kinase C-epsilon