C-reactive protein (CRP) is the prototypic marker of inflammation. Numerous studies in healthy volunteers have confirmed that CRP predicts cardiovascular events and is a risk marker. Also recent studies support a role for CRP in atherogenesis. CRP has been shown to induce cell adhesion molecules, chemokines and endothelin-1 in endothelial cells (EC) and reactive oxygen species, cytokines and tissue factor in monocytes. We have recently shown that CRP directly inhibits the expression and bioactivity of endothelial nitric-oxide synthase (eNOS) in human aortic endothelial cells and augments monocyte-endothelial cell adhesion. Furthermore we have also shown that CRP inhibits prostacyclin release and stimulates PAl-1 release from human aortic EC. Thus the central hypothesis of this proposal is that CRP promotes atherothrombosis via effects on both endothelial cells and monocytes.
In Specific Aim 1 we will examine the mechanisms via which CRP decreases eNOS expression and activity in human aortic and coronary artery endothelial cells.
In Specific Aim 2, we will test the effect of CRP on monocyte endothelial cell adhesion under both static and defined shear flow conditions and will delineate the molecular mechanisms involved.
In Specific Aim 3 we will determine if the processing of CRP is receptor mediated and if this accounts for its biological effects. Finally in Specific Aim 4, we will use Sprague-Dawley and Zucker rats to confirm our findings in vivo. We will test the effect of CRP in vivo on endothelial vasoreactivity, on low density lipoprotein retention and on macrophage biology including cellular adhesion molecule expression, secretion of tissue factor, matrix metalloproteinases and foam cell formation. Thus, these studies will clearly provide us with further scientific evidence in support of the role of CRP in atherothrombosis. ? ?
|Dasu, Mohan R; Jialal, Ishwarlal (2013) Amelioration in wound healing in diabetic toll-like receptor-4 knockout mice. J Diabetes Complications 27:417-21|
|Jialal, Ishwarlal; Kaur, Harmeet; Devaraj, Sridevi et al. (2013) Human C-reactive protein induces endothelial dysfunction in biobreeding diabetic rats. Diab Vasc Dis Res 10:550-3|
|Jialal, I; Devaraj, S; Smith, G et al. (2013) A novel peptide inhibitor attenuates C-reactive protein's pro-inflammatory effects in-vivo. Int J Cardiol 168:3909-12|
|Jialal, I; Machha, A; Devaraj, S (2013) Small interfering-RNA to protein kinase C-delta reduces the proinflammatory effects of human C-reactive protein in biobreeding diabetic rats. Horm Metab Res 45:326-8|
|Jialal, Ishwarlal; Kaur, Harmeet; Devaraj, Sridevi (2013) Human C-reactive protein accentuates macrophage activity in biobreeding diabetic rats. J Diabetes Complications 27:23-8|
|Kaur, Harmeet; Chien, Alexander; Jialal, Ishwarlal (2012) Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am J Physiol Renal Physiol 303:F1145-50|
|Jialal, Ishwarlal; Devaraj, Sridevi (2012) Circulating versus cellular biomarkers of inflammation in Type 1 diabetes: the superiority of C-reactive protein. Cytokine 60:318-20|
|Jialal, Ishwarlal; Devaraj, Sridevi (2012) Antisense to protein kinase C-alpha and p47phox attenuates the pro-inflammatory effects of human C-reactive protein in macrophages of biobreeding diabetic rats. Diab Vasc Dis Res 9:315-9|
|Devaraj, Sridevi; Kumaresan, Pappanaicken R; Jialal, Ishwarlal (2011) C-reactive protein induces release of both endothelial microparticles and circulating endothelial cells in vitro and in vivo: further evidence of endothelial dysfunction. Clin Chem 57:1757-61|
|Devaraj, Sridevi; Siegel, David; Jialal, Ishwarlal (2011) Statin therapy in metabolic syndrome and hypertension post-JUPITER: what is the value of CRP? Curr Atheroscler Rep 13:31-42|
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