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(Circulation. 2006;114:I-206 – I-213.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Therapeutic Delivery of Cyclin A2 Induces Myocardial Regeneration and Enhances Cardiac Function in Ischemic Heart Failure

Y. Joseph Woo, MD; Corinna M. Panlilio, BA; Richard K. Cheng, MD; George P. Liao, MB; Pavan Atluri, MD; Vivian M. Hsu, BA; Jeffrey E. Cohen, BA; Hina W. Chaudhry, MD

From Division of Cardiothoracic Surgery (Y.J.W., C.M.P., G.P.L., P.A., V.M.H., J.E.C.), Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa; Division of Cardiology (R.K.C., H.W.C.), Department of Medicine, Columbia University School of Medicine, New York, NY.

Correspondence to Y. Joseph Woo, Division of Cardiothoracic Surgery, University of Pennsylvania, 3400 Spruce St, Philadelphia PA 19104.E-mail: wooy{at}uphs.upenn.edu

Background— Heart failure is a global health concern. As a novel therapeutic strategy, the induction of endogenous myocardial regeneration was investigated by initiating cardiomyocyte mitosis by expressing the cell cycle regulator cyclin A2.

Methods and Results— Lewis rats underwent left anterior descending coronary artery ligation followed by peri-infarct intramyocardial delivery of adenoviral vector expressing cyclin A2 (n =32) or empty adeno-null (n =32). Cyclin A2 expression was characterized by Western Blot and immunohistochemistry. Six weeks after surgery, in vivo myocardial function was analyzed using an ascending aortic flow probe and pressure-volume catheter. DNA synthesis was analyzed by proliferating cell nuclear antigen (PCNA), Ki-67, and BrdU. Mitosis was analyzed by phosphohistone-H3 expression. Myofilament density and ventricular geometry were assessed. Cyclin A2 levels peaked at 2 weeks and tapered off by 4 weeks. Borderzone cardiomyocyte cell cycle activation was demonstrated by increased PCNA (40.1±2.6 versus 9.3±1.1; P<0.0001), Ki-67 (46.3±7.2 versus 20.4±6.0; P<0.0001), BrdU (44.2±13.7 versus 5.2±5.2; P<0.05), and phosphohistone-H3 (12.7±1.4 versus 0±0; P<0.0001) positive cells/hpf. Cyclin A2 hearts demonstrated increased borderzone myofilament density (39.8±1.1 versus 31.8±1.0 cells/hpf; P=0.0011). Borderzone wall thickness was greater in cyclin A2 hearts (1.7±0.4 versus 1.4±0.04 mm; P<0.0001). Cyclin A2 animals manifested improved hemodynamics: Pmax (70.6±8.9 versus 60.4±11.8 mm Hg; P=0.017), max dP/dt (3000±588 versus 2500±643 mm Hg/sec; P<0.05), preload adjusted maximal power (5.75±4.40 versus 2.75±0.98 mWatts/µL²; P<0.05), and cardiac output (26.8±3.7 versus 22.7±2.6 mL/min; P=0.004).

Conclusions— A therapeutic strategy of cyclin A2 expression via gene transfer induced cardiomyocyte cell cycle activation yielded increased borderzone myofilament density and improved myocardial function. This approach of inducing endogenous myocardial regeneration provides proof-of-concept evidence that cyclin A2 may ultimately serve as an efficient, alternative therapy for heart failure.

Key Words: cyclin • heart failure • myocardial regeneration