Background-All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport-independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury. Methods and Results-In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by Ϸ20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL-and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P 3 lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P 3 -deficient mice. Conclusions-Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/ reperfusion injury in vivo via an S1P 3 -mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia. Key Words: lipoproteins Ⅲ inflammation Ⅲ apoptosis Ⅲ endothelium Ⅲ sphingolipids Ⅲ microcirculation Ⅲ reperfusion T he main therapeutic goals in patients with acute myocardial infarction are to minimize myocardial damage, improve cardiac repair, and reduce myocardial remodeling. State-of-the-art therapy is rapid reperfusion of the infarcted myocardium through revascularization of the occluded vessel. However, the benefit of reperfusion is compromised by the endothelial injury and inflammation that follow reinstitution of blood flow, leading to additional myocardial damage, a process termed "ischemia/reperfusion injury." Despite all efforts to prevent the sequelae of reperfusion injury in Clinical Perspective p 1409 patients, 1 there are currently no clinical strategies available to effectively protect cardiac tissue from the inflammatory damage inherent to reperfusion. 2 High-density lipoproteins (HDLs) are the most powerful independent negative predictor of cardiovascular events evident in all large prospective epidemiological studies. The constituents of the HDL particle that mediate its diverse biological effects are still under investigation. 8 Recently, we and others have identified several sphingolipids, such as sphingosine-1-phosphate (S1P), as constituents of human HDL and have found them responsible for part of the nitric oxide (NO)-mediated vasodilatory effect of HDL. 9 -11 Acute administration of reconstituted HDL has been shown to normalize the en...

Background-After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI. Methods and Results-Experimental MI was induced in wild-type (WT) and bgn Ϫ/0 mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn Ϫ/0 mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn Ϫ/0 mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn Ϫ/0 mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn Ϫ/0 mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn

Background: Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-ODN) initiate an innate immune response mediated by the pattern recognition receptor Toll-like receptor 9 (TLR9). This leads in particular to the expression of proinflammatory mediators such as tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β). TLR9 is expressed in human and murine pulmonary tissue and induction of proinflammatory mediators has been linked to the development of acute lung injury. Therefore, the hypothesis was tested whether CpG-ODN administration induces an inflammatory response in the lung via TLR9 in vivo.

Bbeta15-42 elicits cardioprotection in pigs and is clinically safe in phase I testing of humans. This study confirms the new concept of a pathogenic role of fibrin derivatives in myocardial reperfusion injury, which can be inhibited by peptide Bbeta15-42.