Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although cardiomyocyte (CM) apoptosis has been well described in both in vitro and in vivo models of ischemic heart disease, the intracellular pathways leading to CM death have not been fully characterized. To define the role of death receptor signaling in CM apoptosis, we constructed recombinant adenoviral vectors carrying wild-type (wt) or dominant negative (dn) forms of the death receptor adaptor protein FADD (Fas-associated death domain protein) and used these vectors to transduce rat neonatal CMs in models of hypoxia- and serum deprivation (SD)-induced apoptosis. The combination of SD and hypoxia induced rapid activation of caspase-3 and -8 as well as DNA fragmentation, reaching a plateau within 4-8 h. Adenoviral expression of FADD-dn inhibited caspase-8 activation as well as hypoxia/SD-induced apoptosis at 24 h in an moi (multiplicity of infection)-dependent manner. In contrast, adenoviral expression of FADD-wt increased apoptosis and caspase-3 activity in CMs under both normoxic and hypoxic conditions. Surprisingly, FADD-dn, as well as the specific caspase-8 inhibitor benzyloxycarbonyl-IETD-fluoromethylketone also inhibited the activation of caspase-9 and -3 in CMs subjected to hypoxia/SD. These data suggest a primary role for FADD/caspase-8 signaling that is necessary and sufficient for apoptosis of CMs subjected to hypoxia/SD.
 ...
PMID:Importance of FADD signaling in serum deprivation- and hypoxia-induced cardiomyocyte apoptosis. 1206 58

Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs. Coronary artery occlusion induced a rapid myocardial IRAK-1 activation within 30 min in wild-type (WT), TLR2(-/-), or Trif(-/-) mice, but not in TLR4(def) or MyD88(-/-) mice. HSP60 protein was markedly increased in serum or in perfusate of isolated heart following ischemia/reperfusion (I/R). In vitro, recombinant HSP60 induced IRAK-1 activation in cells derived from WT, TLR2(-/-), or Trif(-/-) mice, but not from TLR4(def) or MyD88(-/-) mice. Both myocardial ischemia- and HSP60-induced IRAK-1 activation was abolished by anti-HSP60 antibody. Moreover, HSP60 treatment of cardiomyocytes (CMs) led to marked activation of caspase-8 and -3, but not -9. Expression of dominant-negative mutant of Fas-associated death domain protein or a caspase-8 inhibitor completely blocked HSP60-induced caspase-8 activation, suggesting that HSP60 likely activates an apoptotic program via the death-receptor pathway. In vivo, I/R-induced myocardial apoptosis and cytokine expression were significantly attenuated in TLR4(def) mice or in WT mice treated with anti-HSP60 antibody compared with WT controls. Taken together, the current study demonstrates that myocardial ischemia activates an innate immune signaling via HSP60 and TLR4, which plays an important role in mediating apoptosis and inflammation during I/R.
 ...
PMID:Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4. 2177 38