Review articleRole of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: Mechanisms and therapeutic implications
Highlights
► Inflammatory cytokines participate in the regulation of coronary vasomotor function. ► Vascular inflammation is involved in microcirculatory obstruction and hyperpermeability. ► Reduced coronary blood flow and inadequate microcirculatory perfusion lead to I/R injury.
Introduction
Coronary blood flow (CBF) regulation in myocardial ischemia/reperfusion (I/R), particularly perfusion at the microcirculatory level, is critical to the outcome of ischemic heart disease. Coronary vascular tone is a crucial factor influencing CBF. The impaired vasodilatory response of coronary arteries during I/R injury was first documented by Ku et al. in 1982 [1]. To date, a variety of vasodilators and vasoconstrictors including endothelium-derived vasoactive factors, autacoids, metabolic messengers, and neurohormonal factors are found to be involved in the regulation of coronary vascular resistance and are emerging as therapeutic targets for the restoration of CBF following I/R injury. In addition to the enhanced vascular constriction, the dysregulation of coronary microcirculatory function during myocardial I/R, which is characterized by microembolization, inflammatory cell infiltration and hyperpermeability, lead to reduced CBF and inadequate myocardial reperfusion. A number of inflammatory cytokines and inflammatory cells are actively involved in the regulation of coronary vascular resistance and microcirculatory function. Elucidating the role of inflammation in CBF dysregulation in myocardial I/R would facilitate the development of novel therapeutics and improve clinical outcomes. Within this context, this review focuses on: (1) the role of inflammation in the regulation of coronary vascular resistance and CBF; (2) the role of inflammation in coronary microcirculatory dysfunction in myocardial I/R injury.
Section snippets
Inflammation and the regulation of coronary vascular resistance in I/R
Coronary vascular resistance serves as a primary determinant of CBF. Regulation of coronary vascular tone is the result of a balance between a myriad of vasodilator and vasoconstrictor signals, in which endothelium-derived vasoactive factors, metabolic messengers, neurohormones, and various autocoids are crucially involved.
Inflammation and coronary microvascular dysfunction in I/R
The aim of thrombolysis, angioplasty, and coronary artery bypass surgery is to restore CBF; however, successful restoration of epicardial coronary artery patency may not always lead to adequate reperfusion at the microvascular level [52], [53], primarily due to microvascular dysfunction caused by coronary microembolization, inflammatory cell infiltration, and impaired microvascular integrity following I/R injury.
Perspectives
Although great progress has been made in elucidating the mechanisms of CBF regulation in myocardial I/R injury, we are experiencing a failure in the translation of these exciting scientific results to patients. First, it remains unclear if myocardial I/R injury occurs to the same extent in man as it does in animal models; the experimental models of myocardial I/R are lacking certain aspects that are frequently present in the clinical environment [52]. Second, results from mice and rats may not
Sources of funding
This study was supported by grants from NIH grants (RO1-HL077566 and RO1-HL085119 to C.Z.) and American Heart Association Predoctoral Fellowship (10PRE4300043 to H.Z.).
Disclosures
None.
Acknowledgments
N/A
References (82)
- et al.
Plasma nitric oxide end products are increased in the ischemic canine heart
Biochem Biophys Res Commun
(1995) - et al.
A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs
J Am Coll Cardiol
(1999) - et al.
L-arginine reduces endothelial inflammation and myocardial stunning during ischemia/reperfusion
Ann Thorac Surg
(1995) - et al.
Cardiac allograft preservation using donor-shed blood supplemented with L-arginine
J Heart Lung Transplant
(2005) - et al.
Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans
J Mol Cell Cardiol
(2005) - et al.
Effects of calcium channel blockers on coronary vasoconstriction induced by endothelin-1 in closed chest pigs
J Am Coll Cardiol
(1990) - et al.
Investigating the dual nature of endothelin-1: ischemia or direct arrhythmogenic effect?
Life Sci
(2000) - et al.
A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II)
J Am Coll Cardiol
(2005) - et al.
Selective activation of E-type prostanoid(3)-receptors reduces myocardial infarct size. A novel insight into the cardioprotective effects of prostaglandins
Pharmacol. Ther.
(2000) - et al.
Constriction of a large coronary artery contributes to serotonin-induced myocardial ischemia in the dog with pliable coronary stenosis
J Am Coll Cardiol
(1989)
Microvascular obstruction: underlying pathophysiology and clinical diagnosis
J Am Coll Cardiol
Reperfusion injury: experimental evidence and clinical implications
Am Heart J
Role of the beta2-integrins and immunoglobulin superfamily members in myocardial ischemia–reperfusion
Ann Thorac Surg
Activation of NF kappa B and expression of ICAM-1 in ischemic–reperfused canine myocardium
J Mol Cell Cardiol
Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia–reperfusion injury by reducing inflammation
Am J Pathol
Myeloperoxidase enhances nitric oxide catabolism during myocardial ischemia and reperfusion
Free Radic Biol Med
Relation between neutrophil counts on admission, microvascular injury, and left ventricular functional recovery in patients with an anterior wall first acute myocardial infarction treated with primary coronary angioplasty
Am J Cardiol
Activated neutrophils induce hyperpermeability and phosphorylation of adherens junction proteins in coronary venular endothelial cells
J Biol Chem
Coronary vascular reactivity after acute myocardial ischemia
Science
Modulation of coronary autoregulatory responses by nitric oxide. Evidence for flow-dependent resistance adjustments in conscious dogs
Circ Res
Physiologically tolerable insulin reduces myocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs
J Cardiovasc Pharmacol
Vasculoprotective effect of insulin in the ischemic/reperfused canine heart: role of Akt-stimulated NO production
Cardiovasc Res
Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to bradykinin- and NO-dependent mechanisms in dogs
Circulation
Angiotensin-converting enzyme inhibition preserves endothelium-dependent coronary microvascular responses during short-term ischemia–reperfusion
Circulation
3′,4′-Dihydroxyflavonol reduces infarct size and injury associated with myocardial ischaemia and reperfusion in sheep
Br J Pharmacol
Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway
J Cardiovasc Pharmacol
Endothelial nitric oxide synthase in vascular disease: from marvel to menace
Circulation
TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury
Arterioscler Thromb Vasc Biol
TNF-alpha contributes to endothelial dysfunction by upregulating arginase in ischemia/reperfusion injury
Arterioscler Thromb Vasc Biol
Direct relationship between levels of TNF-alpha expression and endothelial dysfunction in reperfusion injury
Basic Res Cardiol
Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function
Am J Physiol
Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury
Cardiovasc Res
Inducible nitric oxide synthase expression and cardiomyocyte dysfunction during sustained moderate ischemia in pigs
Circ Res
L-arginine effects on myocardial stress in cardiac surgery: preliminary results
Ital Heart J
L-arginine administration prevents reperfusion-induced cardiomyocyte hypercontracture and reduces infarct size in the pig
Cardiovasc Res
Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide
Circulation
Anti-inflammatory effects of sphingosine kinase modulation in inflammatory arthritis
J Immunol
Meyer zu Heringdorf D, ter Braak M, Hajji N, Olthof DC, et al. Activation of sphingosine kinase by muscarinic receptors enhances NO-mediated and attenuates EDHF-mediated vasorelaxation
Basic Res Cardiol
Role of EDHF in type 2 diabetes-induced endothelial dysfunction
Am J Physiol Heart Circ Physiol
Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway
Circulation
Impaired coronary flow and left ventricular dysfunction after mechanical recanalization in acute myocardial infarction: role of neurohumoral activation?
Basic Res Cardiol
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Authors contributed equally to this work.