Mitogen-Activated Protein Kinase Inhibition and Cardioplegia-Cardiopulmonary Bypass Reduce Coronary Myogenic Tone

Abstract

Background— Cardioplegia-cardiopulmonary bypass (C/CPB) is associated with coronary microcirculatory dysfunction. Regulation of the microcirculation includes myogenic tone. Mitogen-activated protein kinases (MAPK) have been implicated in coronary vasomotor function. We hypothesized that vasomotor dysfunction of the coronary microcirculation is mediated in part by alterations in extracellular signal regulated kinase 1/2 (ERK1/2) activity following C/CPB in humans. Methods and Results— Atrial myocardium was harvested from patients (n=15) before and after blood cardioplegia and short-term reperfusion under conditions of CPB. Myogenic tone of coronary arterioles was measured by videomicroscopy. Microvessel tone was determined post-C/CPB and after PD98059, a MAPK/ERK kinase 1/2 (MEK1/2) inhibitor. MAPK phosphatase-1 (MKP-1) and activated ERK1/2 were measured by Western blot. MKP-1 gene expression was determined by Northern blot. In situ hybridization and immunohistochemistry were used to localize myocardial MKP-1 and activated ERK1/2, respectively. Myogenic tone was reduced in coronary arterioles post-C/CPB (−10.5±0.9%, P <0.01 versus control/pre-C/CPB, n=5). Myogenic tone was decreased in coronary microvessels after 30 μmol/L (n=5) and 50 μmol/L (n=5) PD98059 treatment (−11.0±0.8% and −14.6±2.0%, respectively, both P <0.01 versus control/pre-C/CPB). Myocardial levels of activated ERK1/2 were reduced post-C/CPB (0.6±0.1, post/pre-C/CPB ratio, P <0.05, n=5) while MKP-1 levels increased (4.2±0.6, post/pre-C/CPB ratio, P <0.05, n=5). Myocardial MKP-1 gene expression increased post-C/CPB (3.0±0.8, post/pre-C/CPB ratio, P <0.05, n=5). MKP-1 and activated ERK1/2 localized to coronary arterioles in myocardial sections. Conculsions— Coronary myogenic tone is dependent on ERK1/2 and decreased after C/CPB. C/CPB reduces levels of activated ERK1/2, potentially by increased levels of MKP-1. The ERK1/2 signal transduction pathway in part mediates coronary microvascular dysfunction after C/CPB in humans.