Mitogen-activated protein kinase inhibition and cardioplegia-cardiopulmonary bypass reduce coronary myogenic tone

Article; Proceedings Paper

关键词: SMOOTH-MUSCLE;    ANGIOTENSIN-II;    MAPK;    CONSTRICTION;    CONTRACTION;    REACTIVITY;    PATHWAY;   

DOI  :  10.1161/01.cir.0000087652.93751.0e

来源: SCIE

【 摘 要 】

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 mu mol/L ( n = 5) and 50 mu mol/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.

【 授权许可】

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