In the previous proposal, the central hypothesis was to determine if CRP promotes atherothrombosis by effects on both endothelial cells and monocytes. We have now executed all four aims of this proposal and have advanced the field with regards to the vascular effects of CRP. In summary, we have elucidated the molecular mechanism by which CRP inhibits eNOS (in-vitro and in-vivo), we have documented the role of Fc-gamma receptors in the biological effects of CRP on endothelial cells, macrophages and in Wistar rats. Furthermore, we have elucidated the mechanism of CRPinduced monocyte adhesion under shear stress, and finally we have confirmed in-vivo, in Wistar rats, that CRP has effects that promote atherosclerosis including stimulation of NADPH-oxidase, superoxide, MPO release, oxidized LDL uptake, tissue factor, MMP-9 release from macrophages and decreased vasoreactivity. Diabetes is a proinflammatory state that is characterized by high CRP levels. However, there is a paucity of data examining the role of CRP in promoting the pro-inflammatory state in diabetes. We have shown in exciting and novel preliminary data that CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant effects in the diabetic milieu (spontaneously diabetic BB rat). Thus, in this competing renewal, we wish to further explore the effects of CRP on diabetes and atherothrombosis. To this end, we are proposing two specific aims.
In specific aim 1, we will continue to expand our exciting preliminary findings that CRP accentuates the pro-inflammatory, pro-oxidant state in the diabetic BB rat. In this model, we will confirm if CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant effects in the diabetic milieu and also elucidate the molecular mechanism (s) by which CRP exerts these effects by employing in-vivo siRNA and antisense oligonucleotides to the different pathways identified. Based on findings largely from our group and others, that CRP promotes a pro-coagulant phenotype, in Specific Aim 2, using the spontaneously diabetic BB rat, we will now test in-vivo the effect of CRP on thrombosis in the diabetic milieu. Also, we will elucidate the mechanism (s) by which CRP promotes atherothrombosis in the diabetic state. We believe these studies will provide further novel data in support of the hypothesis that CRP promotes atherothrombosis in-vivo and a procoagulant, pro-inflammatory phenotype in diabetes. Probing into the molecular mechanisms by which CRP augments oxidative stress and inflammation in the diabetic milieu will eventually lead to therapies targeted at reducing inflammation and oxidative stress in diabetes and resulting in a decrease in vasculopathies

Public Health Relevance

Jialal, Ishwarlal Project Narrative-Public Relevance Inflammation is important in all stages of heart disease. In this proposal, we wish to examine the mechanisms by which CRP, the prototypic marker of inflammation in man, actually contributes to plaque formation. We will examine also how this protein promotes inflammation in diabetes, a worldwide epidemic. Finally, we hypothesize that patients with metabolic syndrome and high CRP do worse than those with low CRP, this proposal will identify cellular dysfunction (monocytes and endothelial progenitor cells) that contribute to increased risk in these patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Hasan, Ahmed AK
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University of California Davis
Schools of Medicine
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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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