Atherosclerosis is the leading cause of death in the developed countries. Diabetes mellitus markedly increases the risk of atherosclerotic complications. Emerging evidence suggests that resistin, a novel adipokine implicated in insulin resistin, contributes to atherosclerotic disease and the poor interventional outcomes among diabetic population. We and others have shown that resistin significantly induces vascular smooth muscle cell (VSMC) dysfunction, a key step in intimal hyperplasia and restenosis. However, little is known about the underlying mechanisms and the treatment option is largely lacking. Recently, we demonstrated that the cellular effect of resistin was mediated by PKC-[. Our research team also showed that activating PKC-? protected against ischemia/reperfusion injury of transplanted myocardium and inhibiting PKC-? mitigated intimal hyperplasia in rat. Although therapeutically targeting PKC-? in the treatment of atherosclerotic complications is largely unknown. Based on our novel, seemingly controversial observations, we believe that the involvement of PKC-? in cardiovascular disease is a dynamic process. Acute activation of PKC-? protects against ischemia/reperfusion-induced cellular injuries whereas sustained inhibition of PKC-? following procedures can minimize resistin-induced intimal hyperplasia and restenosis. It is our fundamental hypothesis that time-specific PKC-? modulation reduces resistin-induced intimal hyperplasia and restenosis. To pursue this hypothesis, we propose a more comprehensive investigation to elucidate the molecular mechanisms, cellular effects, and in vivo influences of PKC-? modulation in resistin-exaggerated cellular stress following vascular injury.
Three specific aims (SA) are proposed. SA 1: Determine the role of PKC-? in resistin-induced cellular effects. In this SA, we will first confirm our preliminary findings and determine time-specific PKC-? modulation in VSMC. We will then explore the modulating effect of PKC-? using a novel activated macrophage-VSMC co-culture system. Lastly, we will verify the effects of resistin and PKC-? modulation in ex vivo human carotid plaques. SA 2: Characterize the molecular mechanisms of PKC-?-dependent resistin-induced cellular distress. Using a HCASMC model, we will study the involvement of PKC-? in resistin-induced ROS over-production in the SA2a. We will also expand our preliminary observation by examining time-specific PKC-? modulation in known resistin-induced signaling pathways in SA2b. Lastly, we will explore novel PKC-?-dependent downstream signaling pathway(s) using an unbiased proteomics approach and determine whether a novel PKC-?-mediated molecular interaction, mitochondria aldehyde dehydrogenase (ALDH2), is involved in resistin- induced cellular dysfunction (SA2c). SA 3: Evaluate the effects PKC-? on resistin-augmented post-injury intimal hyperplasia in a murine model. We will independently modulate PKC-? before atrial clamping and after vascular interventions to determine the in vivo effects of time-specific PKC-? modulation on resistin-exacerbated intimal hyperplasia using a transgenic murine model. The potential application of novel PKC-? specific peptide modulators at specific time points, justified by successful completion of our aims, represents a novel therapeutic option. Deciphering clinically-relevant mechanism(s) of intimal hyperplasia and ultimately translating these into a novel therapeutic strategy to suppress disease progression supports our long-term goal of minimizing complications of cardiovascular diseases and improving the clinical outcome of cardiovascular procedures.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001398-03
Application #
8698299
Study Section
Cardiovascular Studies A (CARA)
Project Start
2012-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Admin Palo Alto Health Care Sys
Department
Type
DUNS #
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Zuniga, Mary C; Raghuraman, Gayatri; Zhou, Wei (2018) Physiologic levels of resistin induce a shift from proliferation to apoptosis in macrophage and VSMC co-culture. Surgery 163:906-911
Zuniga, Mary C; Raghuraman, Gayatri; Hitchner, Elizabeth et al. (2017) PKC-epsilon and TLR4 synergistically regulate resistin-mediated inflammation in human macrophages. Atherosclerosis 259:51-59
Raghuraman, Gayatri; Hsiung, Joseph; Zuniga, Mary C et al. (2017) Eotaxin Augments Calcification in Vascular Smooth Muscle Cells. J Cell Biochem 118:647-654
Zuniga, Mary C; Tran, Thuy B; Baughman, Brittanie D et al. (2016) A Prospective Evaluation of Systemic Biomarkers and Cognitive Function Associated with Carotid Revascularization. Ann Surg 264:659-65
Raghuraman, Gayatri; Zuniga, Mary C; Yuan, Hai et al. (2016) PKC? mediates resistin-induced NADPH oxidase activation and inflammation leading to smooth muscle cell dysfunction and intimal hyperplasia. Atherosclerosis 253:29-37
Dannull, Jens; Tan, Chunrui; Farrell, Christine et al. (2015) Gene Expression Profile of Dendritic Cell-Tumor Cell Hybrids Determined by Microarrays and Its Implications for Cancer Immunotherapy. J Immunol Res 2015:789136
Hu, Fangyao; Vishwanath, Karthik; Beumer, H Wolfgang et al. (2014) Assessment of the sensitivity and specificity of tissue-specific-based and anatomical-based optical biomarkers for rapid detection of human head and neck squamous cell carcinoma. Oral Oncol 50:848-856
Zuniga, Mary C; White, Sharla L Powell; Zhou, Wei (2014) Design and utilization of macrophage and vascular smooth muscle cell co-culture systems in atherosclerotic cardiovascular disease investigation. Vasc Med 19:394-406
Ding, Richard Qinxue; Tsao, Jerry; Chai, Hong et al. (2011) Therapeutic potential for protein kinase C inhibitor in vascular restenosis. J Cardiovasc Pharmacol Ther 16:160-7
Ding, Qinxue; White, Sharla Powell; Ling, Christina et al. (2011) Resistin and cardiovascular disease. Trends Cardiovasc Med 21:20-7

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