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.
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:
1. To evaluate the role of arginase as a regulator of NO bioavailability and in endothelial and red blood cells.
2. 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.
3. 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.
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.
Cortese-Krott MM, Mergia E, Kramer CM, Lückstädt W, Yang J, Wolff G, Panknin C, Bracht T, Sitek B, Pernow J, Stasch JP, Feelisch M, Koesling D, Kelm M. Identification of a soluble guanylate cyclase in RBCs: preserved activity in patients with coronary artery disease. Redox Biol. 2018 Apr;14:328-337.
Basalay MV, Mastitskaya S, Mrochek A, Ackland GL, Del Arroyo AG, Sanchez J, Sjoquist PO, Pernow J, Gourine AV, Gourine A. Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning. Cardiovasc Res. 2016 Dec;112(3):669-676.
Kiss A, Tratsiakovich Y, Mahdi A, Yang J, Gonon AT, Podesser BK, Pernow J. Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and down-regulation of cardiac and vascular arginase. Acta Physiol (Oxf). 2017 Nov;221(3):174-181.
Kövamees O, Shemyakin A, Checa A, Wheelock CE, Lundberg JO, Östenson C-G, Pernow J. Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes mellitus. J Clin Endocrin Met. 2016 Nov;101(11):3952-3958..
Verouhis D, Sörensson P, Gourine A, Henareh L, Persson J, Saleh N, Settergren M, Sundqvist M, Tornvall P, Witt N, Böhm F, Pernow J. Effect of remote ischemic conditioning on infarct size in patients with anterior ST-elevation myocardial infarction. Am Heart J.2016 Nov;181:66-73.
Kövamees O, Shemyakin A, Eriksson M, Angelin B, Pernow J. Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels. J Intern Med. 2016 May;279(5):477-84.4.
Kiss A, Tratsiakovich Y, Gonon AT, Fedotovskaya O, Lanner JT, Andersson DC, Yang J, Pernow J. The role of arginase and rho kinase in cardioprotection from remote ischemic perconditioning in non-diabetic and diabetic rat in vivo. PLoS One 2014 Aug 20;9(8):e104731.
Kövamees O, Shemyakin A, Pernow J. Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus. PLoS One. 2014 Jul 29;9:e103260.
Yang J, Gonon AT, Sjöquist PO, Lundberg JON, Pernow J. Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15049-54.
Shemyakin A, Kövamees O, Rafnsson A, Böhm F, Svenarud P, Settergren M, Jung C, Pernow J. Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus. Circulation. 2012 Dec 18;126(25):2943-50.
Ammirati E, et al. Identification and Predictive Value of IL6(+)IL10(+) and IL6(-)IL10(+) Cytokine Patterns in ST-Elevation Acute Myocardial Infarction. Circ Res. 2012 Oct 26;111:1336-48.
Rafnsson A, Böhm F, Settergren M, Gonon A, Brismar K, Pernow J. The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial. Diabetologia. 2012 Mar;55(3):600-7.
Shemyakin A, Salehzadeh F, Esteves Duque-Guimaraes D, Böhm F, Rullman E, Gustafsson T, Pernow J, Krook A. Endothelin-1 reduces glucose uptake in human skeletal muscle in vivo and in vitro. Diabetes. 2011 Aug;60(8):2061-7.
Grönros J, Jung C, Lundberg JON, Östenson C-G, Pernow J. Arginase Inhibition Restores in vivo Coronary Microvascular Function in Type 2 Diabetic Rats. Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1174-81.
Sörensson P, Saleh N, Bouvier F, Böhm F, Settergren M, Caidahl K, Tornvall P, Arheden H, Rydèn L, Pernow J. Effect of postconditioning on myocardial infarct size in patients with ST-elevation myocardial infarction. Heart. 2010 Nov;96(21):1710-5.
Jung C, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J. Arginase inhibition mediates cardioprotection during ischaemia-reperfusion. Cardiovasc Res. 2010 Jan 1;85(1):147-54.