Therapeutic Delivery of Cyclin A2 Induces Myocardial Regeneration and Enhances Cardiac Function in Ischemic Heart Failure
- 4 July 2006
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 114 (1_suppleme), I-206-I-213
- https://doi.org/10.1161/circulationaha.105.000455
Abstract
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 P P P P =0.0011). Borderzone wall thickness was greater in cyclin A2 hearts (1.7±0.4 versus 1.4±0.04 mm; P P =0.017), max dP/dt (3000±588 versus 2500±643 mm Hg/sec; P 2 ; P 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.Keywords
This publication has 25 references indexed in Scilit:
- Forced expression of the cyclin B1–CDC2 complex induces proliferation in adult rat cardiomyocytesBiochemical Journal, 2004
- Cyclin A2 Mediates Cardiomyocyte Mitosis in the Postmitotic MyocardiumPublished by Elsevier BV ,2004
- Local myocardial overexpression of growth hormone attenuates postinfarction remodeling and preserves cardiac functionThe Annals of Thoracic Surgery, 2004
- Breaking Down Cell-Cycle Barriers in the Adult HeartCirculation Research, 2004
- Ethyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemiaThe Journal of Thoracic and Cardiovascular Surgery, 2004
- Adult Cardiac Sca-1-positive Cells Differentiate into Beating CardiomyocytesPublished by Elsevier BV ,2004
- Adult Cardiac Stem Cells Are Multipotent and Support Myocardial RegenerationCell, 2003
- Regulation of Expression and Activity of Distinct pRB, E2F, D-Type Cyclin, and CKI Family Members during Terminal Differentiation of P19 CellsExperimental Cell Research, 1998
- Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo.JCI Insight, 1997
- Expression and Activities of Cyclins and Cyclin-dependent Kinases in Developing Rat Ventricular MyocytesJournal of Molecular and Cellular Cardiology, 1997