This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 96/7/767    most recent 01.RES.0000162099.01268.d1v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, G. Articles by Canty, J. M. Search for Related Content PubMed PubMed Citation Articles by Suzuki, G. Articles by Canty, J. M., Jr Related Collections Animal models of human disease Growth factors/cytokines Chronic ischemic heart disease Gene therapy Related Article

(Circulation Research. 2005;96:767.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Adenoviral Gene Transfer of FGF-5 to Hibernating Myocardium Improves Function and Stimulates Myocytes to Hypertrophy and Reenter the Cell Cycle

Gen Suzuki, Te-Chung Lee, James A. Fallavollita, John M. Canty, Jr

From the VA WNY Health Care System and the Departments of Medicine and Physiology and Biophysics and the Center for Research in Cardiovascular Medicine at the University at Buffalo, Buffalo, NY.

Correspondence to John M. Canty, Jr, Division of Cardiology, University at Buffalo, Biomedical Research Building, Room 347, 3435 Main Street, Buffalo, NY 14214. E-mail canty{at}buffalo.edu

Fibroblast growth factors (FGFs) have diverse actions on the myocardium but the importance of stimulating angiogenesis versus direct effects of FGFs on cardiac myocytes is unclear. We used intracoronary injection of a replication-deficient adenoviral construct overexpressing FGF-5 (AdvFGF-5) to improve flow and function in swine with hibernating myocardium. Two-weeks after AdvFGF-5 (n=8), wall-thickening increased from 2.4±0.04 to 4.7±0.7 mm in hibernating LAD regions (P<0.05) whereas remote wall-thickening was unchanged (6.7±0.4 to 5.8±0.5 mm). This was associated with small increases in resting flow to dysfunctional myocardium, but flow during adenosine was unchanged (LAD 1.45±0.27 versus 1.46±0.23 mL/min per g and remote 4.84±0.23 versus 4.71±0.47 mL/min per g, P=NS). Unexpectedly, animals receiving AdvFGF-5 demonstrated a 29% increase in LV mass over the 2-week period (P<0.05 versus untreated animals with hibernating myocardium and normal shams). Histological analysis confirmed profound myocyte cellular hypertrophy in AdvFGF-5 treated myocardium (19.9±0.32 versus 15.2±0.92 µm in untreated, P<0.001). Myocytes in the proliferative phase of the cell cycle (Ki-67 staining) increased 7-fold after AdvFGF-5 (2,904±405 versus 409±233 per 10⁶ myocyte nuclei in untreated, P<0.05). Myocyte nuclei in the mitotic phase (phosphorylated histone H3 staining) also increased after AdvFGF-5 (127±24 versus 35±13 per 10⁶ myocyte nuclei in untreated, P<0.05). Thus, rather than angiogenesis, stimulation of hypertrophy and reentry of a small number of myocytes into the mitotic phase of the cell cycle are responsible for the effects of AdvFGF-5 on function. Although additional mechanisms may contribute to the improvement in wall-thickening, overexpression of AdvFGF-5 may afford a way to restore function in hibernating myocardium and ameliorate heart failure in chronic ischemic cardiomyopathy.

Key Words: hibernating myocardium • growth factors • gene therapy

Related Article:

FGF Induces Hypertrophy and Angiogenesis in Hibernating Myocardium

Stephen F. Vatner
Circ. Res. 2005 96: 705-707. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				D. Zisa, A. Shabbir, M. Mastri, G. Suzuki, and T. Lee Intramuscular VEGF repairs the failing heart: role of host-derived growth factors and mobilization of progenitor cells Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2009; 297(5): R1503 - R1515. [Abstract] [Full Text] [PDF]

				Q. Hu, G. Suzuki, R. F. Young, B. J. Page, J. A. Fallavollita, and J. M. Canty Jr. Reductions in mitochondrial O2 consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H223 - H232. [Abstract] [Full Text] [PDF]

				A. Shabbir, D. Zisa, G. Suzuki, and T. Lee Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1888 - H1897. [Abstract] [Full Text] [PDF]

				R. Bolli and B. Dawn The Cornucopia of "Pleiotropic" Actions of Statins: Myogenesis As a New Mechanism for Statin-Induced Benefits? Circ. Res., January 30, 2009; 104(2): 144 - 146. [Full Text] [PDF]

				G. Suzuki, V. Iyer, T. Cimato, and J. M. Canty Jr Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle Circ. Res., January 30, 2009; 104(2): 255 - 264. [Abstract] [Full Text] [PDF]

				S. Sidhu, A. Gangasani, L. G. Korotchkina, G. Suzuki, J. A. Fallavollita, J. M. Canty Jr., and M. S. Patel Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H946 - H952. [Abstract] [Full Text] [PDF]

				M. Carlsson, N. F. Osman, P. C. Ursell, A. J. Martin, and M. Saeed Quantitative MR measurements of regional and global left ventricular function and strain after intramyocardial transfer of VM202 into infarcted swine myocardium Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H522 - H532. [Abstract] [Full Text] [PDF]

				H. J. Evans-Anderson, C. M. Alfieri, and K. E. Yutzey Regulation of Cardiomyocyte Proliferation and Myocardial Growth During Development by FOXO Transcription Factors Circ. Res., March 28, 2008; 102(6): 686 - 694. [Abstract] [Full Text] [PDF]

				B. Page, R. Young, V. Iyer, G. Suzuki, M. Lis, L. Korotchkina, M. S. Patel, K. M. Blumenthal, J. A. Fallavollita, and J. M. Canty Jr Persistent Regional Downregulation in Mitochondrial Enzymes and Upregulation of Stress Proteins in Swine With Chronic Hibernating Myocardium Circ. Res., January 4, 2008; 102(1): 103 - 112. [Abstract] [Full Text] [PDF]

				P. Lynch, T.-C. Lee, J. A. Fallavollita, J. M. Canty Jr, and G. Suzuki Intracoronary Administration of AdvFGF-5 (Fibroblast Growth Factor-5) Ameliorates Left Ventricular Dysfunction and Prevents Myocyte Loss in Swine With Developing Collaterals and Ischemic Cardiomyopathy Circulation, September 11, 2007; 116(11_suppl): I-71 - I-76. [Abstract] [Full Text] [PDF]

				M. D. Banas, S. Baldwa, G. Suzuki, J. M. Canty Jr., and J. A. Fallavollita Determinants of contractile reserve in viable, chronically dysfunctional myocardium Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2791 - H2797. [Abstract] [Full Text] [PDF]

				Y. J. Woo, C. M. Panlilio, R. K. Cheng, G. P. Liao, E. E. Suarez, P. Atluri, and H. W. Chaudhry Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2 J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 927 - 933. [Abstract] [Full Text] [PDF]

				Y. J. Woo, C. M. Panlilio, R. K. Cheng, G. P. Liao, P. Atluri, V. M. Hsu, J. E. Cohen, and H. W. Chaudhry Therapeutic Delivery of Cyclin A2 Induces Myocardial Regeneration and Enhances Cardiac Function in Ischemic Heart Failure Circulation, July 4, 2006; 114(1_suppl): I-206 - I-213. [Abstract] [Full Text] [PDF]

				S. F. Vatner FGF Induces Hypertrophy and Angiogenesis in Hibernating Myocardium Circ. Res., April 15, 2005; 96(7): 705 - 707. [Full Text] [PDF]