Protein Tyrosine Kinase Is Not Involved in the Infarct Size–Limiting Effect of Ischemic Preconditioning in Canine Hearts

Abstract

Protein kinase C (PKC) plays an important role in ischemic preconditioning (IP). Because (1) tyrosine kinase is located at the downstream of PKC for IP in the rabbit hearts and (2) we have reported that ecto-5'-nucleotidase is the substrate for PKC and plays a crucial role for the infarct size-limiting effect, we tested whether tyrosine kinase activation contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect of the early phase of IP in the canine heart. In dogs, the IP procedure (4 cycles of 5-minute occlusion of coronary artery) and exposure to 12, 13-phorbol myristate acetate (PMA) each activated myocardial ecto-5'-nucleotidase and Lck tyrosine kinase. Genistein (10, 30, and 100 microg. kg(-)(1). min(-)(1) IC), an inhibitor of tyrosine kinase, attenuated the activation of Lck tyrosine kinase but did not attenuate the activation of ecto-5'-nucleotidase due to either IP or PMA. In the other canine hearts, IP attenuated infarct size (49+/-5 versus 11+/-3 or 16+/-3%, P<0.01) due to 90 minutes of coronary occlusion followed by 6 hours of reperfusion, which was not blunted by 3 or 2 (30 and 100 microg. kg(-)(1). min(-)(1)) doses of genistein (infarct sizes, 15+/-4, 13+/-4, and 13+/-3%, respectively, and 17+/-3 and 15+/-4%, respectively) or lavendustin A. Tyrosine kinase does not activate ecto-5'-nucleotidase or trigger the infarct size-limiting effect of the early phase of IP in canine hearts.

STAT signaling in ischemic heart: a role of STAT5A in ischemic preconditioning

“…A role of tyrosine kinases in preconditioning is widely recognized, and as mentioned above, Src kinase appears to play an essential role in transmitting preconditioning-mediated survival signal. However, there is some evidence indicating that both Src kinase-dependent and Src kinase-independent signal transduction pathways exist based on the observation that protein tyrosine kinase is not involved in the infarct size-limiting effect of early preconditioning in the canine heart (9). Consistent with this report, we found activation of STAT3 via JAK could also lower the myocardial infarct size induced by preconditioning (21).…”

Ischemic preconditioning: emerging evidence, controversy, and translational trials

“…p38MAPK activation requires dual phosphorylation of its 180T-X-Y182 site, but the mechanism by which ischemia transiently activates p38MAPK is unclear. Some reports have suggested that both PKC [43,54] and some tyrosine kinases [24] may play a role, but we found that tyrosine kinase activation was unrelated to cardioprotection in dogs [56], at least with regard to the early phase of ischemic preconditioning. This issue should be investigated further.…”

Protein Kinase A as Another Mediator of Ischemic Preconditioning Independent of Protein Kinase C

“…4 However, preischemic PKC activation had little influence on IPinduced Rho-kinase inhibition in this study, showing the limited contribution of PKC to this pathway. Furthermore, we have reported 27 that Src/Lck tyrosine kinase is not involved in the infarct limitation by IP in this model. Although it did not …”