Abstract

AA metabolites derived via lipoxygenase (LO) mainly 12(S)-hydroxyeicosatetraenoic acid (HETE) and cytochrome P450 (CYP450) (20-HETE), pathways, cause vasoconstriction, vascular smooth muscle cell (VSMC) hyperplasia and/or hypertrophy. However, the mechanism by which these AA metabolites promote vascular remodeling during injury is not well understood. Our preliminary observations that a) spleen tyrosine kinase (p72Syk), a non-receptor tyrosine kinase, is also expressed in rat VSMC and it is activated by AA and its metabolites 5(S)-, 12(S)-, 15(S) and 20-HETE and also Ang II (which causes release of AA); b) inhibitors of p38 mitogen activated protein kinase (MAPK) and PKCzeta minimize Ang II-induced p72 Syk activation; c) AA and HETEs, like Ang II, promote neointima formation in balloon injured rat carotid artery; and d) Ang I induced neointima formation in the injured artery is attenuated by dominant negative p72 Syk have led us to the following central hypothesis: AA and its metabolites, mainly HETEs, promote neointima formation and stenosis by activating p72 Syk via activation of p38 MAPK and PKCzeta through the epidermal growth factor receptor (EGFR). To test this hypothesis, the following specific aims will be considered:
Aim 1. To determine the expression and activation of p72 Syk by AA and its metabolite and Ang II in VSMC.
Aim 2. To examine the relationship between AA and its metabolites and ERK1/2, p38MAPK, JNK, PKCzeta, EGFR and p72 Syk in VSMC.
Aim. 3. To investigate the contribution of p72 Syk to neointima formation by AA and its metabolites (HETEs) and of Ang II to in vivo in balloon injured rat carotid artery.
Aim 4. To determine the contribution of p72 Syk in vitro to VSMC-migration, proliferation, hypertrophy and extracellular matrix production in response to AA, HETEs, and Ang II. The proposed studies should advance our knowledge of the mechanism involved in vascular remodeling during injury and provide a rational approach for the development of novel agents for the treatment vascular diseases including restenosis and atherosclerosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079109-03
Application #
7162636
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Goldman, Stephen
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$346,086
Indirect Cost

  Institution

Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163

  Publications

Michael, Christie F; Waters, Christopher M; LeMessurier, Kim S et al. (2017) Airway Epithelial Repair by a Prebiotic Mannan Derived from Saccharomyces cerevisiae. J Immunol Res 2017:8903982
Pingili, Ajeeth K; Davidge, Karen N; Thirunavukkarasu, Shyamala et al. (2017) 2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice. Hypertension 69:1104-1112
Thirunavukkarasu, Shyamala; Khan, Nayaab S; Song, Chi Young et al. (2016) Cytochrome P450 1B1 Contributes to the Development of Angiotensin II-Induced Aortic Aneurysm in Male Apoe(-/-) Mice. Am J Pathol 186:2204-2219
Pingili, Ajeeth K; Thirunavukkarasu, Shyamala; Kara, Mehmet et al. (2016) 6?-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice. Hypertension 67:916-26
Song, Chi Young; Ghafoor, Khuzema; Ghafoor, Hafiz U et al. (2016) Cytochrome P450 1B1 Contributes to the Development of Atherosclerosis and Hypertension in Apolipoprotein E-Deficient Mice. Hypertension 67:206-13
Pingili, Ajeeth K; Kara, Mehmet; Khan, Nayaab S et al. (2015) 6?-hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II-induced hypertension and its pathogenesis in male mice. Hypertension 65:1279-87
Lavrentyev, Eduard N; Malik, Kafait U (2009) High glucose-induced Nox1-derived superoxides downregulate PKC-betaII, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs. Am J Physiol Heart Circ Physiol 296:H106-18
Yaghini, Fariborz A; Li, Fang; Malik, Kafait U (2007) Expression and mechanism of spleen tyrosine kinase activation by angiotensin II and its implication in protein synthesis in rat vascular smooth muscle cells. J Biol Chem 282:16878-90
Parmentier, Jean-Hugues; Zhang, Chunxiang; Estes, Anne et al. (2006) Essential role of PKC-zeta in normal and angiotensin II-accelerated neointimal growth after vascular injury. Am J Physiol Heart Circ Physiol 291:H1602-13
Yaghini, Fariborz A; Zhang, Chunxiang; Parmentier, Jean-Hugues et al. (2005) Contribution of arachidonic acid metabolites derived via cytochrome P4504A to angiotensin II-induced neointimal growth. Hypertension 45:1182-7