Table 5.
PKC Isoforms Involved in Specific Vascular Diseases and PKC Modulators Used as Potential Therapeutic Tools in Clinical Trials
| PKC | Vascular Disease | Role of PKC | Drug | Effect on PKC | Outcome | Comments | Reference |
|---|---|---|---|---|---|---|---|
| PKCβ | Diabetic Retinopathy | Detrimental. Cytokine activation and inhibition, vascular alterations, cell cycle and transcriptional factor dysregulation, abnormal angiogenesis, increased matrix protein synthesis | Ruboxistaurin | Inhibit | Reduced sustained moderate vision loss in large studies | Under review by FDA for diabetic retinopathy | (Tuttle et al., 2005; Vinik et al., 2005; Geraldes and King, 2010; Aiello et al., 2011; Mochly-Rosen et al., 2012) |
| Ruboxistaurin | Inhibit | Failed to improve kidney outcomes | Studied as secondary outcome in large retinopathy trials | ||||
| Ruboxistaurin | Inhibit | Mild decrease in symptoms | Requires validation in larger study | ||||
| PKCδ | Ischemic Heart Disease | Detrimental. Increases ROS production, decreases ATP generation, increases apoptosis and necrosis | Delcasertib for acute myocardial infarction (MI) | Inhibit | No benefit when given intravenously | Positive biomarker trend when given to patients with TIMI 0/1 flow | (Inagaki et al., 2003; Churchill and Mochly-Rosen, 2007; Bates et al., 2008; Mochly-Rosen et al., 2012) |
| KAI-9803: Phase I clinical trial, intracoronary injection during primary percutaneous coronary intervention | Selective PKCδ RACK antagonist | Signs of potential drug activity (not dose-dependent) | Acceptable safety and tolerability | ||||
| PKCɛ | Ischemic Heart Disease | Protective. Protection of mitochondrial functions & proteasomal activity, activation of ALDH2 and reduction of aldehydic load | Adenosine for acute MI | ↑PKCɛ | Reduced infarct size from 27% to 11% when given at 70 mcg/kg/min | No reduction in composite endpoint of death and CHF | (Mochly-Rosen and Kauvar, 2000; Ross et al., 2005; Budas et al., 2007; Chen et al., 2008; Mochly-Rosen et al., 2012) |
| Adenosine for coronary bypass grafting | ↑PKCɛ | Reduction in composite AMI, mortality, need for pressors postoperatively. | Requires validation in larger study | ||||
| Acadesine for coronary bypass grafting | ↑PKCɛ | Reduced two year mortality in the small group of patients who had a post-operative acute MI. | No reduction in death, acute MI, or stroke |