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Published on: July 6, 2015
Mitogen-activated protein kinase contributes to elevated basal tone in aortic smooth muscle from hypertensive rats
Junghwan Kim1, Youn R Lee, Chang-Hun Lee
1Department of Physiology, College of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Danwol-dong 322, Choongju 380-701, Korea.
Abstract:
The role of mitogen-activated protein kinase (MAPK) in increased basal tone -spontaneous resistance in vascular muscle strips- was clarified in aortic smooth muscle from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The MAPK/extracellular signal-regulated protein kinase (ERK) kinase inhibitor, PD098059 (2'-amino-3'-methoxyflavone), significantly inhibited basal tone in a dose-dependent manner. The basal level of ERK1/2 activation was inhibited by PD098059 and was significantly greater in hypertensive rats than in sham-operated rats. In contrast, inhibition with PD098059 was not observed in sham-operated rats. GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide), an inhibitor of protein kinase C (PKC), decreased both basal tone and ERK1/2 activity in the hypertensive rats. In contrast, Y27632 ((R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide) and verapamil, inhibitors of Rho kinase and voltage-dependent Ca2+ channels, respectively, significantly inhibited basal tone but not ERK1/2 activity. Thus, basal vascular tone is elevated by the altered activation of MAPK in DOCA-salt hypertensive rats, and this is regulated by PKC, but not by Rho or intracellular Ca2+.
Insights
Mitogen-activated protein kinase (MAPK) pathway activation elevates basal vascular tone in deoxycorticosterone acetate (DOCA)-salt hypertension. This process is regulated by protein kinase C (PKC), not Rho kinase or calcium channels.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Pharmacology
Background:
- Hypertension is characterized by elevated vascular tone.
- The signaling pathways contributing to sustained increases in vascular tone are not fully understood.
- Mitogen-activated protein kinase (MAPK) pathways are implicated in vascular smooth muscle function.
Purpose of the Study:
- To investigate the role of MAPK/extracellular signal-regulated protein kinase (ERK) in elevated basal vascular tone in deoxycorticosterone acetate (DOCA)-salt hypertensive rats.
- To elucidate the upstream regulators of MAPK/ERK activation in this hypertensive model.
Main Methods:
- Aortic smooth muscle strips from DOCA-salt hypertensive and sham-operated rats were used.
- The effects of specific inhibitors (PD098059 for MAPK/ERK kinase, GF109203X for protein kinase C (PKC), Y27632 for Rho kinase, verapamil for Ca2+ channels) on basal tone and ERK1/2 activation were assessed.
- Western blotting was used to measure ERK1/2 activation levels.
Main Results:
- The MAPK/ERK kinase inhibitor PD098059 dose-dependently inhibited basal tone and ERK1/2 activation in DOCA-salt hypertensive rats.
- Basal ERK1/2 activation was significantly higher in hypertensive rats compared to controls.
- PKC inhibition (GF109203X) reduced both basal tone and ERK1/2 activity in hypertensive rats.
- Rho kinase (Y27632) and Ca2+ channel (verapamil) inhibition reduced basal tone but did not affect ERK1/2 activity.
Conclusions:
- Elevated basal vascular tone in DOCA-salt hypertension is mediated by altered MAPK/ERK activation.
- Protein kinase C (PKC) plays a regulatory role in this MAPK-dependent pathway.
- Rho kinase and intracellular calcium do not appear to be the primary regulators of basal tone in this model.
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