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(Circulation. 2005;112:I-190 – I-195.)
© 2005 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Bradykinin Preconditioning Improves the Profile of Cell Survival Proteins and Limits Apoptosis After Cardioplegic Arrest

Jun Feng, MD, PhD; Cesario Bianchi, MD, PhD; Jennifer L. Sandmeyer, BS; Frank W. Sellke, MD

From the Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass.

Correspondence to Dr Frank W. Sellke, Division of Cardiothoracic Surgery, BIDMC, LMOB 2A, 110 Francis St, Boston, MA 02215. E-mail fsellke{at}caregroup.harvard.edu

Background— We hypothesized that preconditioning the heart with bradykinin (BK) would improve the profile of antiapoptotic proteins and inhibit myocardial apoptosis.

Methods and Results— Eighteen rabbit hearts were retrogradely perfused with Krebs-Henseleit buffer (KHB). Six control hearts were perfused with KHB for 90 minutes without cardioplegia ischemia. Six hearts were arrested for 30 minutes (37°C) with crystalloid cardioplegia (CCP). Six BK preconditioning (BKPC) hearts received a 10-minute coronary infusion of 10^–8 M BK-enriched KHB followed by a 5-minute recovery period and were then arrested for 30 minutes with CCP. The hearts were reperfused for 30 minutes with KHB. BKPC significantly improved the recovery of left ventricular pressure (73±5 versus 51±4 mm Hg; P<0.05) and reduced the percentage of myocardial apoptosis (3.4±0.3% versus 1.2±0.2%; P<0.05) as compared with CCP. There were no significant differences in total protein levels of caspase 3, Bcl-2, Bad, and Bax, among the groups. Both BKPC and CCP induced phosphorylation of Bad at Ser¹¹², but the BKPC group had higher phosphorylated Bad than CCP (4.4±0.5 versus 2.0±0.3; P<0.05). Both BKPC and CCP alone increased caspase 3 cleavage and activity as compared with controls (P<0.05 and P<0.01, respectively), but BKPC caused less cleavage and activation of caspase 3 than CCP alone (P<0.05).

Conclusions— BKPC increased Bad phosphorylation, inhibited caspase 3 activation, and limited myocardial apoptosis, which were associated with improvement of left-ventricular performance. These results identify novel molecular mechanisms underlying the protective effects of BKPC during cardiac surgery.

Key Words: apoptosis • bradykinin • cardioplegia • ischemia • protein