Myocardial stunning is the transient cardiac dysfunction that follows brief episodes of ischemia and reperfusion without associated myocardial necrosis. Currently, there is limited knowledge about its cellular and biochemical mechanisms. In order to better understand the underlying mechanisms of contractile dysfunction associated with the stunning, comprehensive proteomic studies using 2-D DIGE were performed using a regional stunning model in canine heart. Cardiac myosin binding protein C (cMyBP-C), a regulatory myofilament protein associated with the thick filament, and nebulette, a thin filament associated protein, were differentially expressed. Phosphoprotein specific staining indicated both protein changes were due to phosphorylation. Subsequent phosphorylation mapping of canine cMyBP-C using IMAC and MS/MS identified five phosphorylation sites, including three novel sites. In order to further evaluate this finding in a different model, cMyBP-C phosphorylation was examined in a rat model of global stunning. In the rat model, stunning was associated with increased phosphorylation of cMyBP-C at a critical calcium/calmodulin-dependent kinase II site, and the increased phosphorylation was largely inhibited when stunning was prevented by either ischemic preconditioning or reperfusion in the presence of low-calcium buffer. These data indicate cMyBP-C phosphorylation plays an important role in myocardial stunning.
Recent studies have found that selective stimulation of troponin (Tn)I protein kinase A (PKA) phosphorylation enhances heart rate-dependent inotropy and blunts relaxation delay coupled to increased afterload. However, in failing hearts, TnI phosphorylation by PKA declines while protein kinase C (PKC) activity is enhanced, potentially augmenting TnI PKC phosphorylation. Accordingly, we hypothesized that these site-specific changes deleteriously affect both rate-responsive cardiac function and afterload dependence of relaxation, both prominent phenotypic features of the failing heart. A transgenic (TG) mouse model was generated in which PKA-TnI sites were mutated to mimic partial dephosphorylation (Ser22 to Ala; Ser23 to Asp) and dominant PKC sites were mutated to mimic constitutive phosphorylation (Ser42 and Ser44 to Asp). The two highest-expressing lines were further characterized. TG mice had reduced fractional shortening of 34.7 +/- 1.4% vs. 41.3 +/- 2.0% (P = 0.018) and slight chamber dilation on echocardiography. In vivo cardiac pressure-volume studies revealed near doubling of isovolumic relaxation prolongation with increasing afterload in TG animals (P < 0.001), and this remained elevated despite isoproterenol infusion (PKA stimulation). Increasing heart rate from 400 to 700 beats/min elevated contractility 13% in TG hearts, nearly half the response observed in nontransgenic animals (P = 0.005). This blunted frequency response was normalized by isoproterenol infusion. Abnormal TnI phosphorylation observed in cardiac failure may explain exacerbated relaxation delay in response to increased afterload and contribute to blunted chronotropic reserve.
Hofmann. Acute p38 MAPK activation decreases force development in ventricular myocytes. Am J Physiol Heart Circ Physiol 285: H2578-H2586, 2003. First published July 24, 2003 10.1152/ajpheart.00365.2003.-Evidence suggests that p38 mitogen-activated protein kinase (MAPK) activation influences cardiac function on an acute basis. The characterization and mechanisms by which this occurs were investigated in the present study. Adult rat ventricular myocytes treated with 1 mM arsenite for 30 min had a 16-fold increase in p38 MAPK phosphorylation that was attenuated by SB-203580 (a p38 MAPK inhibitor). Extracellular signal-regulated protein kinase (ERK) and c-Jun NH 2-terminal kinase (JNK) were also minimally activated, but this activation was not sensitive to SB-203580. In addition, arsenite caused a p38 MAPK-independent translocation/activation of protein phosphatase 2a (PP2a) and decrease in phosphorylation of myosin light chain 2 (LC2). Arsenite-p38 MAPK activation led to translocation of heat shock protein 27 but not ␣B-crystallin to the myofilaments. Using isolated cardiomyocytes, we determined that arsenite reduces isometric tension without a change in Ca 2ϩ sensitivity of tension via p38 MAPK and lowers myofibrillar actomyosin Mg 2ϩ -ATPase activity in a p38 MAPK-independent manner. Thus arsenite induces a p38 MAPK-independent change in PP2a and LC2 that may account for the arsenite-dependent decrease in ATPase and a p38 MAPK-dependent modification of the myofilaments that decreases myocardial force development. mitogen-activated protein kinase; phosphatase; ␣B-crystallin; heat shock protein 27; light chain 2; isometric force; calcium sensitivity of tension MITOGEN-ACTIVATED PROTEIN kinase (MAPK) signal transduction pathways, which are an integral part of a cell's stress response, work through changes in gene transcription and protein expression. However, a growing number of studies also suggest there are posttranslational effects of MAPK activation on cell and tissue functions. Specifically, the 38-kDa MAPK (p38 MAPK) has been implicated in causing posttranslational modifications and immediate translocation of cytosolic proteins to cytoskeletal elements and other nonnuclear domains. For example, p38 MAPK-dependent phosphorylation of heat shock protein 27 (HSP-27) triggers reorganization of F-actin in vascular endothelial cells (18). This in turn may modulate cell permeability and migration. In the heart, p38 MAPK activation causes an immediate decrease in developed pressure (25), and p38 MAPK has been implicated in both improving and exacerbating ischemia-reperfusion damage observed directly after ischemia (1, 37). The present study focuses on understanding if and how p38 MAPK activation influences cardiac function over the short term.p38 MAPK is activated by a number of pharmacological and pathological stimuli in the heart. -Adrenergic (26) and adenosine (17) stimulation, reactive oxygen species (8), pressure overload (15), and ischemia and reperfusion (1, 37) all increase p38 MAPK activation. p38 MAPK activ...
. Chronic xanthine oxidase inhibition prevents myofibrillar protein oxidation and preserves cardiac function in a transgenic mouse model of cardiomyopathy.
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