Thickness dependence of anomalous Nernst coefficient and longitudinal spin Seebeck effect in ferromagnetic NixFe100-x films.

Spin Seebeck effect (SSE) measured for metallic ferromagnetic thin films in commonly used longitudinal configuration contains the contribution from anomalous Nernst effect (ANE). The ANE is considered to arise from the bulk of the ferromagnet (FM) and the proximity-induced FM boundary layer. We fabricate a FM alloy with zero Nernst coefficient to mitigate the ANE contamination of SSE and insert a thin layer of Cu to separate the heavy metal (HM) from the FM to avoid the proximity contribution. These modifications to the experiment should permit complete isolation of SSE from ANE in the longitudinal configuration. However, further thickness dependence studies and careful analysis of the results revealed, ANE contribution of the isolated FM alloy is twofold, surface and bulk. Both surface and bulk contributions, whose magnitudes are comparable to that of the SSE, can be modified by the neighboring layer. Hence surface contribution to the ANE in FM metals is an important effect that needs to be considered.

GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling after acute myocardial infarction in the mouse.

Adenosine (Ado) is released in response to tissue injury, promotes hyperemia, and modulates inflammation. The proinflammatory effects of Ado, which are mediated by the A(2B) Ado receptor (AdoR), may exacerbate tissue damage. We hypothesized that selective blockade of the A(2B) AdoR with 3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione (GS-6201) during acute myocardial infarction (AMI) would reduce adverse cardiac remodeling. Male ICR mice underwent coronary artery ligation or sham surgery (n = 10-12 per group). The selective A(2B) AdoR antagonist GS-6201 (4 mg/kg) was given intraperitoneally twice daily starting immediately after surgery and continuing for 14 days. Transthoracic echocardiography was performed before surgery and after 7, 14, and 28 days. A subgroup of mice was killed 72 h after surgery, and the activity of caspase-1, a key proinflammatory mediator, was measured in the cardiac tissue. All sham-operated mice were alive at 4 weeks, whereas 50% of vehicle-treated mice and 75% of GS-6201-treated mice were alive at 4 weeks after surgery. Compared with vehicle, treatment with GS-6201 prevented caspase-1 activation in the heart at 72 h after AMI (P < 0.001) and significantly limited the increase in left ventricular (LV) end-diastolic diameter by 40% (P < 0.001), the decrease in LV ejection fraction by 18% (P < 0.01) and the changes in the myocardial performance index by 88% (P < 0.001) at 28 days after AMI. Selective blockade of A(2B) AdoR with GS-6201 reduces caspase-1 activity in the heart and leads to a more favorable cardiac remodeling after AMI in the mouse.

Inhibition of apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion injury in the mouse.

BACKGROUND: Despite the clear advantages of reperfusion in acute myocardial infarction, part of the myocardium is injured during reperfusion by reactive oxygen species. Reactive oxygen species activate apoptosis signal-regulating kinase-1, a key mediator in cell death. We hypothesized that inhibition of apoptosis signal-regulating kinase-1 at the time of reperfusion would protect the heart from ischemia-reperfusion injury. METHODS AND RESULTS: Male CD1 mice underwent transient coronary artery ligation (30 minutes) followed by reperfusion or underwent sham surgery (n=10 to 12 per group). A selective small-molecule inhibitor of apoptosis signal-regulating kinase-1 (GS-459679) was given immediately after reperfusion (10 or 30 mg/kg IP). Infarct size was measured early (at 24 hours, in a subgroup of mice) by triphenyl tetrazolium chloride staining and late (at 7 days) by Masson's trichrome staining for fibrosis. Apoptosis was assessed by measurement of caspase-3 activity and by determination of DNA fragmentation in cardiomyocytes bordering the infarct. Transthoracic echocardiography was performed before surgery and then at 24 hours and 7 days later. Treatment with GS-459679 at reperfusion led to a significant dose-related reduction in infarct size (31% for 10 mg/kg [P<0.001 versus vehicle] and 60% for 30 mg/kg [P<0.001 versus vehicle]), inhibition of apoptotic cell death, and preservation of left ventricular dimension and systolic function at both 24 hours and 7 days. CONCLUSIONS: Inhibition of apoptosis signal-regulating kinase-1 at the time of reperfusion limits infarct size and preserves left ventricular function in a model of acute myocardial infarction in the mouse.

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse.

Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.