John Pernow Group
The role of endothelial and red blood cell dysfunction in coronary artery disease and myocardial ischemia-reperfusion injury
Our research is focused on 1) the identification of disease mechanisms and 2) development of novel therapeutic strategies to improve endothelial function in coronary artery disease (CAD) and limit the extent of myocardial infarction. Occurrence of endothelial dysfunction characterized by reduced availability of nitric oxide (NO) is an early factor during development of CAD and tissue injury during ischemia-reperfusion. This is of particular importance in diabetes which considerably increases the risk for CAD. We have identified key regulators of NO including the enzyme arginase that is upregulated in CAD and diabetes and reciprocally regulates NO formation and oxidative stress. Targeting arginase improves endothelial function and protects against myocardial ischemia-reperfusion injury. Our recent data suggest an intriguing role of red blood cell arginase as a critical regulator of NO production and reactive oxygen species both in red blood cells and the vasculature. Future projects will test the hypothesis that inhibition of arginase in the vasculature and red blood cells improves cardiovascular function in CAD and risk factors associated with CAD including diabetes and hypercholesterolemia. Further, we investigate the mechanisms behind and the therapeutic effects of remote ischemic perconditioning (RIPC) i.e. the signalling of cardiac protective effect by brief periods of remote ischemia.
Aims: The overall aim is to identify the key mechanisms regulating the bioavailability of NO in the development of CAD and myocardial ischemia-reperfusion injury. The importance of these mechanisms as therapeutic targets is tested in early interventional studies using disease animal models and clinical cohorts. The following specific objectives are set to be achieved:
- To evaluate the role of arginase as a regulator of NO bioavailability and in endothelial and red blood cells
- To explore the functional importance of endothelial and red blood cell arginase/NO for vascular function and myocardial ischemia-reperfusion in experimental animals and patients with CAD risk factors
- To clarify the mechanisms behind and the therapeutic effect of RIPC in myocardial ischemia-reperfusion injury
Methods and work plan: Experimental studies are performed on isolated heart preparations and in vivo models of myocardial ischemia-reperfusion using control and diabetic rat and mouse models. Isolated hearts are used for detail investigations of red blood cell biology. The therapeutic effect of arginase inhibition is investigated by evaluation of endothelial function in patients with CAD, diabetes and hypercholesterolemia. Molecular signalling and the therapeutic effect of RIPC is investigated in experimental and clinical studies on patients with ST-elevation myocardial infarction.
Significance: The project will provide novel insights into molecular mechanisms driving development of CAD and myocardial ischemia-reperfusion injury. Targets identified in experimental studies are tested in early clinical interventional studies that will provide the basis for novel therapeutic strategies.
Circulation and respiration
Atherosclerosis, Cardiovascular diseases, Diabetes, Myocardial infarction, Obesity
Animal models, Clinical trials, Intervention/therapy, Oxidative stress, Signal transduction