Protein kinase C (PKC) has a central role in the process of signal transduction. In vascular smooth muscle (VSM), PKC has been hypothesized to be involved in the regulation of tonic contraction in a manner distinct from known mechanisms involving regulation of crossbridge activity by phosphorylation of the 20 kilodalton regulatory light chains of myosin. One of the general goals of the proposed research has been to determine whether PKC can be regulated by contractile stimuli in VSM, and if so, to identify specific substrates that are phosphorylated and the functional consequences of this. The studies to date support the concept that contractile stimuli can cause a prolonged activation of PKC in intact arterial smooth muscle. This is based on the measurement of PKC activity associated with membrane fractions isolated from stimulated tissues. It is also clear that other functions linked to PKC activations, for example those related to regulation of cell shape, specific gene expression, and growth are likely to be important from the standpoint of both normal VSM cell physiology and VSM cell pathophysiology. Additional approaches in a model system of cultured rat aortic smooth muscle are proposed to; 1) define the specific isozymes of PKC which are expressed in VSM, their activation properties, and subcellular distribution, 2) determine whether contractile and growth stimuli can alter the abundance and/or activity of specific isozymes in discrete subcellular fractions, and 3) assess the functional consequences of this activation in specific subcellular compartments. Protein kinase C activities have been shown to be elevated in some tissues from hypertensive subjects, and is the receptor for tumor promotor such as phorbol esters. Details regarding this aspect of signal transduction in VSM is likely to be of importance in understanding pathology associated with vascular diseases in which contractile activity is altered, such as hypertension and vasospasm, or in which VSM cell growth is altered, such as atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040992-05
Application #
3358409
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1988-07-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Weis Center for Research-Geisinger Clinc
Department
Type
DUNS #
079161360
City
Danville
State
PA
Country
United States
Zip Code
17822
Ginnan, Roman; Guikema, Benjamin J; Halligan, Katharine E et al. (2008) Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases. Free Radic Biol Med 44:1232-45
Ginnan, Roman; Guikema, Benjamin J; Singer, Harold A et al. (2006) PKC-delta mediates activation of ERK1/2 and induction of iNOS by IL-1beta in vascular smooth muscle cells. Am J Physiol Cell Physiol 290:C1583-91
Ginnan, Roman; Singer, Harold A (2005) PKC-delta-dependent pathways contribute to PDGF-stimulated ERK1/2 activation in vascular smooth muscle. Am J Physiol Cell Physiol 288:C1193-201
Ginnan, Roman; Pfleiderer, Paul J; Pumiglia, Kevin et al. (2004) PKC-delta and CaMKII-delta 2 mediate ATP-dependent activation of ERK1/2 in vascular smooth muscle. Am J Physiol Cell Physiol 286:C1281-9
Ginnan, Roman; Singer, Harold A (2002) CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle. Am J Physiol Cell Physiol 282:C754-61
Rokolya, A; Walsh, M P; Singer, H A et al. (1998) Protein kinase C--catalyzed calponin phosphorylation in swine carotid arterial homogenate. J Cell Physiol 176:545-52
Bhat, G J; Abraham, S T; Singer, H A et al. (1997) Alpha-thrombin stimulates sis-inducing factor-A DNA binding activity in rat aortic smooth muscle cells. Hypertension 29:356-60
Busuttil, S J; Morehouse, D L; Youkey, J R et al. (1996) Antisense suppresssion of protein kinase C-alpha and -delta in vascular smooth muscle. J Surg Res 63:137-42
Schorb, W; Conrad, K M; Singer, H A et al. (1995) Angiotensin II is a potent stimulator of MAP-kinase activity in neonatal rat cardiac fibroblasts. J Mol Cell Cardiol 27:1151-60
Booz, G W; Taher, M M; Baker, K M et al. (1994) Angiotensin II induces phosphatidic acid formation in neonatal rat cardiac fibroblasts: evaluation of the roles of phospholipases C and D. Mol Cell Biochem 141:135-43

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