Research Group John Perow

Our research aims to explore novel mechanisms behind the progression of atherosclerosis and to develop new therapeutic strategies reduce the risk of myocardial infarction. We focus on mechanism causing endothelial dysfunction, especially by the risk factors diabetes and high cholesterol. We are also conducting research on how to limit the injury to the myocardium occurring during a myocardial infarction.

Endothelial dysfunction in atherosclerotic cardiovascular disease

Atherosclerotic cardiovascular disease including coronary artery disease (CAD) and myocardial infarction remains leading cause of morbidity and mortality. Despite recent progress, the mechanisms remain unclear. Occurrence of endothelial dysfunction primarily characterized by reduced availability of nitric oxide (NO) increased oxidative stress is an early factor during development of CAD and tissue injury during ischemia-reperfusion.

Our research is focused on the identification of disease mechanisms behind endothelial dysfunction, and development of novel therapeutic strategies to improve endothelial function in coronary artery disease (CAD) and limit the extent of myocardial infarction.

This is of particular importance in diabetes and hyperlipidemia 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 suggest an intriguing interaction between red blood cells (RBCs) and the endothelium in the development of cardiovascular injury in type 2 diabetes. This effect appears to be driven by increased arginase activity and ROS formation in RBCs in type 2 diabetes.

Endothelial and cardiac injury induced by dysfunctional RBC in type 2 diabetes.
Endothelial and cardiac injury induced by dysfunctional RBC in type 2 diabetes. From the publikation Pernow et al. Cardiovasc Res 2019;115:1596-1605.

Ongoing projects

In ongoing projects we investigate:

  • the effect of RBCs from different patient groups with risk factors for and developed atherosclerotic cardiovascular disease on cardiac and endothelial dysfunction
  • the signaling mechanisms underlying cardiac and vascular injury caused by RBC from patients with and animal models of type 2 diabetes, hypercholesterolemia and myocardial infarction
  • the effect of pharmacological interventions on RBC and endothelial function in these patient groups
  • the impact of co-morbidities on cardioprotective effects of pharmacological and ischemic conditioning on acute myocardial infarction

Research methods and models

We perform translational studies ranging from molecular to clinical studies. Molecular studies are focused on understanding of the role of NO signaling pathway in RBCs, endothelial cells and the vascular wall. Additional approaches are focused on signaling by non-coding RNA. Experimental models include isolated heart preparations, isolated vessels, cell culture and in vivo models of myocardial infarction. We also perform investigations of endothelial function in humans, which include early interventional studies exploring novel targets in patients with CAD and risk factors. Finally, the group performs randomized clinical studies with functional and clinical endpoints.

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.

Research Group members

John Pernow

Professor/senior physician, Research Group Leader and Head of Division
K2 Department of Medicine, Solna

Marita Wallin, BMA Technician

David Ersgård, BMA Technician

Jiangning Yang, Assistant professor

Zhichao Zhou, Assistant professor

Aida Collado Sánchez, Postdoc

Yahor Tratsiakovich, Postdoc

Oskar Kövamees, Postdoc

Ali Mahdi, PhD student

Jiao Tong, PhD student

Tigist Wodaje, PhD student

John Tengbom, PhD student

On site you find us on the 8th floor of BioClinicum, and at clinical research unit at Norrbacka S1: 02 within the hospital area.

Selected key publications

Influenza Vaccination after Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.
Frøbert O, Götberg M, Erlinge D, Akhtar Z, Christiansen EH, MacIntyre CR, Oldroyd KG, Motovska Z, Erglis A, Moer R, Hlinomaz O, Jakobsen L, Engstrøm T, Jensen LO, Fallesen CO, Jensen SE, Angerås O, Calais F, Kåregren A, Lauermann J, Mokhtari A, Nilsson J, Persson J, Stalby P, Islam AKMM, Rahman A, Malik F, Choudhury S, Collier T, Pocock SJ, Pernow J
Circulation 2021 Aug;():

Arginase 1 is upregulated at admission in patients with ST-elevation myocardial infarction.
Tengbom J, Cederström S, Verouhis D, Böhm F, Eriksson P, Folkersen L, Gabrielsen A, Jernberg T, Lundman P, Persson J, Saleh N, Settergren M, Sörensson P, Tratsiakovich Y, Tornvall P, Jung C, Pernow J
J Intern Med 2021 Jul;():

Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD.
Hussain S, Khan AW, Akhmedov A, Suades R, Costantino S, Paneni F, Caidahl K, Mohammed SA, Hage C, Gkolfos C, Björck H, Pernow J, Lund LH, Lüscher TF, Cosentino F
Circ Res 2020 10;127(10):1261-1273

Red Blood Cell Peroxynitrite Causes Endothelial Dysfunction in Type 2 Diabetes Mellitus via Arginase.
Mahdi A, Tengbom J, Alvarsson M, Wernly B, Zhou Z, Pernow J
Cells 2020 07;9(7):

Endothelin-1 increases expression and activity of arginase 2 via ETB receptors and is co-expressed with arginase 2 in human atherosclerotic plaques.
Rafnsson A, Matic LP, Lengquist M, Mahdi A, Shemyakin A, Paulsson-Berne G, et al
Atherosclerosis 2019 Oct;():

Hemoglobin β93 Cysteine Is Not Required for Export of Nitric Oxide Bioactivity From the Red Blood Cell.
Sun CW, Yang J, Kleschyov AL, Zhuge Z, Carlström M, Pernow J, et al
Circulation 2019 Jun;139(23):2654-2663

The Effect of Glycemic Control on Endothelial and Cardiac Dysfunction Induced by Red Blood Cells in Type 2 Diabetes.
Mahdi A, Jiao T, Yang J, Kövamees O, Alvarsson M, von Heijne M, Zhou Z, Pernow J
Front Pharmacol 2019 ;10():861

Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I.
Zhou Z, Mahdi A, Tratsiakovich Y, Zahorán S, Kövamees O, Nordin F, et al
J. Am. Coll. Cardiol. 2018 08;72(7):769-780

Red Blood Cells in Type 2 Diabetes Impair Cardiac Post-Ischemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species.
Yang J, Zheng X, Mahdi A, Zhou Z, Tratsiakovich Y, Jiao T, et al
JACC Basic Transl Sci 2018 Aug;3(4):450-463

Arginase inhibition improves endothelial function in patients with type 2 diabetes mellitus despite intensive glucose-lowering therapy.
Mahdi A, Kövamees O, Checa A, Wheelock CE, von Heijne M, Alvarsson M, et al
J. Intern. Med. 2018 10;284(4):388-398

Oxygen Therapy in Suspected Acute Myocardial Infarction.
Hofmann R, James SK, Jernberg T, Lindahl B, Erlinge D, Witt N, et al
N. Engl. J. Med. 2017 09;377(13):1240-1249

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

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 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 inhibition mediates cardioprotection during ischaemia-reperfusion.
Jung C, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J
Cardiovasc. Res. 2010 Jan;85(1):147-54

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

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