Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/reperfusion injury.
Ischemia/reperfusion (I/R) injury to the heart is accompanied by the upregulation and posttranslational modification of a number of proteins normally involved in regulating cell cycle progression. Two such proteins, cyclin-dependent kinase-2 (Cdk2) and its downstream target, the retinoblastoma gene product (Rb), also play a critical role in the control of apoptosis. Myocardial ischemia activates Cdk2, resulting in the phosphorylation and inactivation of Rb. Blocking Cdk2 activity reduces apoptosis in cultured cardiac myocytes. Genetic or pharmacological inhibition of Cdk2 activity in vivo during I/R injury led to a 36% reduction in infarct size (IFS), when compared to control mice, associated with a reduction in apoptotic myocytes. To confirm that Rb was the critical target in Cdk2-mediated I/R injury, we determined the consequences of I/R injury in cardiac-specific Rb-deficient mice (CRb(L/L)). IFS was increased 140% in CRb(L/L) mice compared to CRb+/+ controls. TUNEL positive nuclei and caspase-3 activity were augmented by 92% and 36%, respectively, following injury in the CRb(L/L) mice demonstrating that loss of Rb in the heart significantly exacerbates I/R injury. These data suggest that Cdk2 signaling pathways are critical regulators of cardiac I/R injury in vivo and support a cardioprotective role for Rb.
Liem
David A
DA
Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Zhao
Peng
P
Angelis
Ekaterini
E
Chan
Shing S
SS
Zhang
Jun
J
Wang
Guangwu
G
Berthet
Cyril
C
Kaldis
Philipp
P
Ping
Peipei
P
MacLellan
W Robb
WR
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction
D016160:Retinoblastoma Protein; D051357:Cyclin-Dependent Kinase 2; D053148:Caspase 3