Background-CXCR4-positive bone marrow cells (BMCs) are critically involved in cardiac repair mechanisms contributing to preserved cardiac function. Stromal cell-derived factor-1 (SDF-1) is the most prominent BMC homing factor known to augment BMC engraftment, which is a limiting step of stem cell-based therapy. After myocardial infarction, SDF-1 expression is rapidly upregulated and promotes myocardial repair. Methods and Results-We have established a bifunctional protein consisting of an SDF-1 domain and a glycoprotein VI (GPVI) domain with high binding affinity to the SDF-1 receptor CXCR4 and extracellular matrix proteins that become exposed after tissue injury. SDF1-GPVI triggers chemotaxis of CXCR4-positive cells, preserves cell survival, enhances endothelial differentiation of BMCs in vitro, and reveals proangiogenic effects in ovo. In a mouse model of myocardial infarction, administration of the bifunctional protein leads to enhanced recruitment of BMCs, increases capillary density, reduces infarct size, and preserves cardiac function. Conclusions-These results indicate that administration of SDF1-GPVI may be a promising strategy to treat myocardial infarction to promote myocardial repair and to preserve cardiac function. (Circulation. 2012;125:685-696.)Key Words: GPVI Ⅲ myocardial infarction Ⅲ cells Ⅲ SDF-1 Ⅲ tissue repair I n recent years, extensive efforts have been made to identify mechanisms to promote myocardial repair and regeneration. 1,2 It has been increasingly recognized that bone marrow (BM)-derived progenitor cells (BMCs) participate in cardiac repair mechanisms and regeneration and contribute to function recovery after myocardial infarction (MI). Elevated levels of BMCs in patients with cardiovascular disease are associated with a reduced risk of death from cardiovascular complications. 3,4 The isolation of putative BMCs was first described in the late 1990s, 5 and it has become evident that circulating BMCs significantly contribute to the regeneration of vascular integrity and support locally induced repair mechanisms of resident endothelial cells. 6 In vivo studies in mice and rats provide evidence that vascular homing of BMCs improves endothelial regeneration and preserves myocardial function after transient coronary ischemia. [7][8][9] Myocardial BMC transplantation into immunodeficient mice induces sustained humoral effects and leads to increased mobilization of endogenous BM-derived or progenitor cells that are incorporated into sites of neovascularization and myocardial repair. 10 Clinical Perspective on p 696Progressive adverse left ventricular (LV) remodeling after MI is the pathomorphological substrate of postinfarction heart failure and reduced survival. 11 Cell therapy for patients with acute MI has been evaluated in the past by various clinical studies. In some studies, intracoronary administration of BMCs has been found to improve recovery of LV contractile function in patients with acute MI. [12][13][14] Other clinical studies did not show a beneficial effect of intracorona...
Myocardial inflammation is critical for ventricular remodeling after ischemia. Phospholipid mediators play an important role in inflammatory processes. In the plasma membrane they are degraded by phospholipase D1 (PLD1). PLD1 was shown to be critically involved in ischemic cardiovascular events. Moreover, PLD1 is coupled to tumor necrosis factor-α signaling and inflammatory processes. However, the impact of PLD1 in inflammatory cardiovascular disease remains elusive. Here, we analyzed the impact of PLD1 in tumor necrosis factor-α-mediated activation of monocytes after myocardial ischemia and reperfusion using a mouse model of myocardial infarction. PLD1 expression was highly up-regulated in the myocardium after ischemia/reperfusion. Genetic ablation of PLD1 led to defective cell adhesion and migration of inflammatory cells into the infarct border zone 24 hours after ischemia/reperfusion injury, likely owing to reduced tumor necrosis factor-α expression and release, followed by impaired nuclear factor-κB activation and interleukin-1 release. Moreover, PLD1 was found to be important for transforming growth factor-β secretion and smooth muscle α-actin expression of cardiac fibroblasts because myofibroblast differentiation and interstitial collagen deposition were altered in Pld1(-/-) mice. Consequently, infarct size was increased and left ventricular function was impaired 28 days after myocardial infarction in Pld1(-/-) mice. Our results indicate that PLD1 is crucial for tumor necrosis factor-α-mediated inflammation and transforming growth factor-β-mediated collagen scar formation, thereby augmenting cardiac left ventricular function after ischemia/reperfusion.
ZusammenfassungMyotone Serien im Elektromyogramm (EMG) gelten als charak− teristischer Befund für myotone Erkrankungen. Elektromyogra− phische Spontanaktivität, die mit myotonen Serien verwechselt werden kann, kommt aber auch bei einer Reihe anderer Erkran− kungen vor, so bei der Neuromyotonie und dem Schwartz−Jam− pel−Syndrom, bei Myositiden, Glykogenosen, einzelnen seltene− ren Myopathien und bei chronisch neurogenen Erkrankungen. Myotone Serien fehlen nie bei den Chloridkanalmyotonien und werden häufig bei Patienten mit einer der myotonen Dystro− phien gefunden. Bei Natriumkanalerkrankungen sind sie meis− tens unprovoziert nachweisbar, gelegentlich aber nur nach loka− ler Muskelkühlung, Arbeits− oder Kaliumbelastung. Sie kommen bei periodischen Paralysen, die nicht auf einer Natriumkanalmu− tation beruhen, nicht vor. Auf dieser Basis werden Hinweise so− wohl zur Differenzialdiagnose der myotonen Dystrophien und der Kanalerkrankungen als auch zur Differenzialdiagnose von Serienentladungen im EMG gegeben. AbstractMyotonic discharges in concentric needle electromyography are often considered to be diagnostic for myotonic disorders. How− ever, electromyographic spontaneous activity that can be mis− taken for myotonic discharges may occur in a variety of other dis− orders, such as neuromyotonia, Schwartz−Jampel syndrome, myosites, glycogenoses, a few rare myopathies, and in chronic neurogenic disorders. Myotonic discharges are always present in chloride channel myotonias and frequently in patients with one of the myotonic dystrophies. Myotonic discharges are a fre− quent finding in patients with sodium channelopathy, but in some patients they occur only by provoking their occurrence via local muscle cooling, work, or potassium load. So far, myotonic discharges have never occurred in patients with periodic paraly− ses not caused by altered sodium channels. Based on this fact we present pointers to differential diagnosis of myotonic dystro− phies and muscle channelopathies as well as to differential diag− nosis of myotonic discharges and similar EMG findings.
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