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Interference of peroxisome proliferator‐activated receptor‐gamma (PPAG) in vascular muscle enhances myogenic tone in small resistance arteries via protein kinase C (PKC)‐induced inhibition of large conductance Ca2+‐activated K+ channel (BKCa) activity
Author(s) -
Ketsawatsomkron Pimonrat,
Lorca Ramon A,
England Sarah K,
Faraci Frank M,
Sigmund Curt D
Publication year - 2012
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.26.1_supplement.1058.6
Subject(s) - myograph , myogenic contraction , medicine , iberiotoxin , endocrinology , protein kinase c , vascular smooth muscle , chemistry , biology , vasodilation , signal transduction , biochemistry , smooth muscle
PPARG is a ligand activated transcription factor expressed in vasculature. Targeted expression of dominant negative PPARG to vascular muscle of transgenic mice (S‐P467L) caused hypertension and aortic dysfunction. We hypothesized that smooth muscle PPARG regulates resistance vessel function. We examined myogenic tone and vascular reactivity in small mesenteric arteries (MA) from S‐P467L and non‐transgenic controls (NT) using a pressurized myograph. MA from S‐P467L exhibited significantly increased myogenic tone (at 100 mmHg: S‐P467L 34.5±1.7%, NT 21.0±2.1%, P<0.05). Iberiotoxin (IbTX), an inhibitor of BKCa, induced constriction in NT MA (at 75 mmHg, 10.1±0.6%) but this effect was markedly blunted in S‐P467L (S‐P467L 5.5±0.9%, P<0.05). Whole‐cell K + current was measured using patch clamp in freshly dissociated smooth muscle cells (SMC) isolated from MA. Total K + current was similar between two groups. However, IbTX only inhibited K + current in NT (from 40.4±5.6 to 25.4±4.1 pA/pF at 100mV, P<0.01) while having no effect in S‐P467L (from 48.8±7.9 to 50.9±8.5 pA/pF at 100 mV). A PKC inhibitor, chelerythrine chloride restored the sensitivity of S‐P467L SMC to IbTX‐induced blockade of K + current. Lastly, inhibition of PKC markedly decreased myogenic tone in S‐P467L. We conclude that interference of PPARG function causes increased vascular tone through a reduced BKCa activity by a PKC dependent mechanism.