Evidence for involvement of the PKC-α isoform in myogenic contractions of the coronary microcirculation

Dessy, Chantal; Matsuda, Noriaki; Hulvershorn, Justin; Sougnez, Carrie; Sellke, Frank W.; Morgan, Kathleen G.

doi:10.1152/ajpheart.2000.279.3.h916

Cited by 52 publications

(48 citation statements)

References 41 publications

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“…These findings pose mechanistic questions about how PKC influences myogenic vasoconstriction. A prior study demonstrated that intraluminal pressure can induce PKC translocation to the smooth muscle plasma membrane in coronary arteries, suggesting that PKC activity is elevated by increasing perfusion pressure (9). Furthermore, PKC inhibition reverses pressure-induced smooth muscle cell depolarization in cerebral arteries, demonstrating that PKC activity contributes to increased arterial myocyte excitability in response to pressure (43).…”

Section: Discussionmentioning

confidence: 97%

Protein kinase C regulates vascular myogenic tone through activation of TRPM4

Earley¹,

Straub²,

Brayden³

2007

American Journal of Physiology-Heart and Circulatory Physiology

142

136

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Earley S, Straub SV, Brayden JE. Protein kinase C regulates vascular myogenic tone through activation of TRPM4. Am J Physiol Heart Circ Physiol 292: H2613-H2622, 2007. First published February 9, 2007; doi:10.1152/ajpheart.01286.2006.-Myogenic vasoconstriction results from pressure-induced vascular smooth muscle cell depolarization and Ca 2ϩ influx via voltage-dependent Ca 2ϩ channels, a process that is significantly attenuated by inhibition of protein kinase C (PKC). It was recently reported that the melastatin transient receptor potential (TRP) channel TRPM4 is a critical mediator of pressureinduced smooth muscle depolarization and constriction in cerebral arteries. Interestingly, PKC activity enhances the activation of cloned TRPM4 channels expressed in cultured cells by increasing sensitivity of the channel to intracellular Ca 2ϩ . Thus we postulated that PKCdependent activation of TRPM4 might be a critical mediator of vascular myogenic tone. We report here that PKC inhibition attenuated pressure-induced constriction of cerebral vessels and that stimulation of PKC activity with phorbol 12-myristate 13-acetate (PMA) enhanced the development of myogenic tone. In freshly isolated cerebral artery myocytes, we identified a Ca 2ϩ -dependent, rapidly inactivating, outwardly rectifying, iberiotoxin-insensitive cation current with properties similar to those of expressed TRPM4 channels. Stimulation of PKC activity with PMA increased the intracellular Ca 2ϩ sensitivity of this current in vascular smooth muscle cells. To validate TRPM4 as a target of PKC regulation, antisense technology was used to suppress TRPM4 expression in isolated cerebral arteries. Under these conditions, the magnitude of TRPM4-like currents was diminished in cells from arteries treated with antisense oligonucleotides compared with controls, identifying TRPM4 as the molecular entity responsible for the PKC-activated current. Furthermore, the extent of PKC-induced smooth muscle cell depolarization and vasoconstriction was significantly decreased in arteries treated with TRPM4 antisense oligonucleotides compared with controls. We conclude that PKC-dependent regulation of TRPM4 activity contributes to the control of cerebral artery myogenic tone. melastatin transient receptor potential; phorbol 12-myristate 13-acetate; cerebral artery myocytes MODULATION OF ARTERIAL TONE in response to changes in intraluminal pressure [often referred to as the vascular myogenic response (3)] is vital for autoregulation of blood flow. Myogenic constriction is mediated by pressure-induced smooth muscle cell depolarization and Ca 2ϩ influx via voltage-dependent Ca 2ϩ channels (VDCCs). Inhibition of protein kinase C (PKC) activity leads to a loss of myogenic tone (13,20,37), suggesting an important role for this pathway in pressuredependent vascular regulation. Further insight into the molecular mechanisms responsible for myogenic constriction was provided by a recent report from our laboratory demonstrating that TRPM4, a member of the transient receptor potential (TRP)...

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Section: Discussionmentioning

confidence: 97%

Protein kinase C regulates vascular myogenic tone through activation of TRPM4

Earley¹,

Straub²,

Brayden³

2007

American Journal of Physiology-Heart and Circulatory Physiology

142

136

View full text Add to dashboard Cite

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“…The mechanistic basis of the myogenic response is calciumdependent activation of the actin-myosin motor unit, as evidenced by a brisk rise in VSM intra-cellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) in response to the mechanostimulus of pressure and by subsequent phosphorylation of myosin light chain kinase (3,22,34). However, other factors also play a role in the initiation and maintenance of myogenic vasoconstriction, reviewed most recently by Davis and Hill (5); of these, that which has direct bearing on the present work is PKC (6,13,15,16,19,27). For example, pressure stimulation applied to coronary arterioles caused a transient increase in [Ca 2ϩ ] i , but a sustained translocation of PKC␣ from cytosol-to-membrane in VSM, indicating its activation (6).…”

mentioning

confidence: 78%

Development of the myogenic response in postnatal intestine: role of PKC

Reber

Nankervis

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Previous attempts to determine developmental changes in the vascular myogenic response have been confounded by the presence of competing vasoactive stimuli or the use of isolated vessels with markedly different baseline diameters. To circumvent these issues, small mesenteric arteries (diameter ∼150 μm) from 1- and 10-day-old piglets were studied in vitro under no-flow conditions. In situ studies demonstrated that the intravascular pressure and diameter of these vessels were similar in both age groups, allowing an effective comparison of the myogenic response not obscured by differences in basal diameter. The pressure-diameter relationship was age specific. Thus, although small mesenteric arteries from both age groups demonstrated myogenic constriction in response to stepwise increases in pressure (0 to 100 mmHg, in 20-mmHg increments), the intensity of contraction was significantly greater in vessels from 1-day-old piglets particularly within the pressure range normally experienced by these vessels in situ. Attenuation or activation of PKC with calphostin C or indolactam, respectively, substantially altered the pressure-diameter relationship in 1-, but not 10-day-old arteries; thus calphostin C essentially eliminated the contractile response to pressure elevation in younger subjects, whereas indolactam significantly increased the intensity of the myogenic response and shifted its activation point to a lower pressure range. Immunoblots carried out on protein recovered from these arteries revealed the presence of α, β, ε, ι, and λ; notably, expression of the α- and ε-isoforms substantially decreased between postnatal days 1 and 10.

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“…Immunohistochemical analysis showed the presence of PKCα and PKCγ in the smooth muscle cells of rat posterior cerebral arteries. PKCα has been shown to mediate agonist-induced and myogenic vasoconstriction (13,34), whereas the role of PKCγ, which is primarily restricted to the central nervous system (35), in vascular smooth muscle cells is little known. Thus, PKCα is more likely to mediate Ca 2+ sensitization in the development of myogenic constriction, as suggested in the ferret coronary microcirculation (34).…”

Section: +mentioning

confidence: 99%

Distinct Roles of Protein Kinase C Isoforms in Myogenic Constriction of Rat Posterior Cerebral Arteries

Kashihara¹,

Nakayama²,

Ishikawa³

2008

J Pharmacol Sci

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Abstract. The involvement of protein kinase C (PKC) in myogenic constriction at physiological intraluminal pressure was investigated in rat posterior cerebral arteries. ] i elevation gradually declined in the presence of rottlerin, and it was nearly abolished by ruthenium red. Immunohistochemical analysis showed positive staining for PKCα, γ, δ, and ε, but not PKCβ, in smooth muscle cells of rat posterior cerebral arteries. These results suggest distinct roles of PKC isoforms in myogenic constriction: conventional PKC mediates Ca 2+ sensitization, whereas PKCδ mediates sustained [Ca 2+ ] i elevation via the activation of cation channels, resulting in sustained constriction.

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Evidence for involvement of the PKC-α isoform in myogenic contractions of the coronary microcirculation

Cited by 52 publications

References 41 publications

Protein kinase C regulates vascular myogenic tone through activation of TRPM4

Protein kinase C regulates vascular myogenic tone through activation of TRPM4

Development of the myogenic response in postnatal intestine: role of PKC

Distinct Roles of Protein Kinase C Isoforms in Myogenic Constriction of Rat Posterior Cerebral Arteries

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