Research group John Pernow
Research group John Pernow
Novel mechanisms and treatments for 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 primarily 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 both by increasing NO production and reducing the formation of reactive oxygen species (ROS). Our recent data in addition 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 interference with these mechanisms 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 and vagal activation in the setting of myocardial ischemia-reperfusion.
Head of Division - John Pernow
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 and vagal activation 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.
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.
On Bioclinicum floor 8 and Norrbacka S1:02
Selected key publications
Comparable potent coronary constrictor effects of endothelin-1 and big endothelin-1 in humans.
Pernow J, Kaijser L, Lundberg JM, Ahlborg G
Circulation 1996 Nov;94(9):2077-82
Dual endothelin receptor blockade acutely improves insulin sensitivity in obese patients with insulin resistance and coronary artery disease.
Ahlborg G, Shemyakin A, Böhm F, Gonon A, Pernow J
Diabetes Care 2007 Mar;30(3):591-6
Adiponectin protects against myocardial ischaemia-reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide.
Gonon AT, Widegren U, Bulhak A, Salehzadeh F, Persson J, Sjöquist PO, et al
Cardiovasc. Res. 2008 Apr;78(1):116-22
Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease.
Settergren M, Böhm F, Rydén L, Pernow J
Eur. Heart J. 2008 Jul;29(14):1753-60
Arginase inhibition mediates cardioprotection during ischaemia-reperfusion.
Jung C, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J
Cardiovasc. Res. 2010 Jan;85(1):147-54
Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus.
Shemyakin A, Kövamees O, Rafnsson A, Böhm F, Svenarud P, Settergren M, et al
Circulation 2012 Dec;126(25):2943-50
Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity.
Yang J, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J
Proc. Natl. Acad. Sci. U.S.A. 2013 Sep;110(37):15049-54
Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels.
Kovamees O, Shemyakin A, Eriksson M, Angelin B, Pernow J
J. Intern. Med. 2016 May;279(5):477-84
Arginase Inhibition Improves Microvascular Endothelial Function in Patients With Type 2 Diabetes Mellitus.
Kövamees O, Shemyakin A, Checa A, Wheelock CE, Lundberg JO, Östenson CG, et al
J. Clin. Endocrinol. Metab. 2016 Nov;101(11):3952-3958
Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and downregulation of cardiac and vascular arginase.
Kiss A, Tratsiakovich Y, Mahdi A, Yang J, Gonon AT, Podesser BK, et al
Acta Physiol (Oxf) 2017 Nov;221(3):174-181