Kallikrein/kinin protects against myocardial apoptosis after ischemia/reperfusion via Akt-glycogen synthase kinase-3 and Akt-Bad.14-3-3 signaling pathways.

Abstract

Our previous study has shown that human tissue kallikrein protected against ischemia/reperfusion-induced myocardial injury. In the present study, we investigated the protective role of local kallikrein gene delivery in ischemia/reperfusion-induced cardiomyocyte apoptosis and its signaling mechanisms in promoting cardiomyocyte survival. Adenovirus carrying the human tissue kallikrein gene was delivered locally into the heart using a catheter-based technique. Expression and localization of recombinant human kallikrein in rat myocardium after gene transfer were determined immunohistochemically. Kallikrein gene delivery markedly reduced reperfusion-induced cardiomyocyte apoptosis identified by both in situ nick end-labeling and DNA fragmentation. Delivery of the kallikrein gene increased phosphorylation of Src, Akt, glycogen synthase kinase (GSK)-3beta, and Bad(Ser-136) but reduced caspase-3 activation in rat myocardium after reperfusion. The protective effect of kallikrein on apoptosis and its signaling mediators was blocked by icatibant and dominant-negative Akt, indicating a kinin B2 receptor-Akt-mediated event. Similarly, kinin or transduction of kallikrein in cultured cardiomyocytes promoted cell viability and attenuated apoptosis induced by hypoxia/reoxygenation. The effect of kallikrein on cardiomyocyte survival was blocked by dominant-negative Akt and a constitutively active mutant of GSK-3beta, but it was facilitated by constitutively active Akt, catalytically inactive GSK-3beta, lithium, and caspase-3 inhibitor. Moreover, kallikrein promoted Bad.14-3-3 complex formation and inhibited Akt-GSK-3beta-dependent activation of caspase-3, whereas caspase-3 administration caused reduction of the Bad.14-3-3 complex, indicating an interaction between Akt-GSK-caspase-3 and Akt-Bad.14-3-3 signaling pathways. In conclusion, kallikrein/kinin protects against cardiomyocyte apoptosis in vivo and in vitro via Akt-Bad.14-3-3 and Akt-GSK-3beta-caspase-3 signaling pathways.

• Authors: Hang Yin, Lee Chao, Julie Chao
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 9 Pg. 8022-30 (Mar 04 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15611141 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 14-3-3 Proteins
• BAD protein, human
• Bad protein, rat
• Carrier Proteins
• DNA, Complementary
• Kinins
• Proto-Oncogene Proteins
• Recombinant Proteins
• bcl-Associated Death Protein
• icatibant
• DNA
• Lithium
• AKT1 protein, human
• Akt1 protein, rat
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Kallikreins
• CASP3 protein, human
• Casp3 protein, rat
• Caspase 3
• Caspases
• Oxygen
• Bradykinin

Topics

• 14-3-3 Proteins (metabolism)
• Adenoviridae (genetics)
• Animals
• Apoptosis
• Blotting, Western
• Bradykinin (analogs & derivatives, pharmacology)
• Carrier Proteins (metabolism)
• Caspase 3
• Caspases (metabolism)
• Cell Survival
• DNA (metabolism)
• DNA Fragmentation
• DNA, Complementary (metabolism)
• Gene Transfer Techniques
• Genes, Dominant
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Hypoxia
• Immunohistochemistry
• Immunoprecipitation
• In Situ Nick-End Labeling
• Ischemia
• Kallikreins (metabolism, physiology)
• Kinins (metabolism, physiology)
• Lithium (metabolism)
• Male
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism)
• Oxygen (metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Rats
• Rats, Wistar
• Recombinant Proteins (chemistry)
• Reperfusion Injury
• Signal Transduction
• bcl-Associated Death Protein