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.
Atherosclerosis is the leading cause of death in the developed countries and restenosis is a common complication that significantly hinders long-term benefits of cardiovascular procedures. Atherosclerotic disease is highly prevalent in the VA population. Although still controversial, resistin is increasingly implicated in the etiology of insulin resistance and has shown to contribute to the poor interventional outcomes among diabetic population. We and others have demonstrated that resistin significantly induces vascular smooth muscle cell dysfunction, a key step in intimal hyperplasia and restenosis. This proposal utilizes a comprehensive molecular, cellular, and animal model approach to investigate the role of time-dependent PKC-? modulation in resistin-exaggerated vascular dysfunction. We hope that our investigation will establish a solid foundation for a large-scale clinical research on the treatment strategies for vascular restenosis in patients with high cardiovascular risks.
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