Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heart.

Abstract

BACKGROUND:

Compared with younger patients, myocardial infarction in the elderly has been associated with less favorable clinical outcomes, which may be attributable to a decline in angiogenic capacity in the aging heart.

METHODS AND RESULTS:

To test the hypothesis that the functional phenotype of cardiac microvascular endothelial cells is maintained partly by a cardiac myocyte platelet-derived growth factor (PDGF)-B-induced paracrine pathway, we conducted in vitro studies with murine cardiac cells. These studies demonstrated that unlike young endothelial cells, endothelial cells of the aging heart do not express PDGF-B when cultured in the presence of cardiac myocytes. The functional significance of this endothelial dysregulation was assessed with an ex vivo pinnal cardiac allograft model to demonstrate that senescent cardiac angiogenic activity was depressed (2 of 17 allografts were viable in 18-month-old mice versus 19 of 20 in 3-month-old mice; P<0.01). PDGF-AB pretreatment specifically restored the viability of the cardiac allografts in the aging hosts (13 of 13 allografts were viable; P<0.01 versus 18-month-old controls). Finally, in vivo studies in rat hearts demonstrated that pretreatment by intramyocardial delivery of PDGF-AB promotes angiogenesis and minimizes the extent of myocardial infarction in the aging hearts after coronary ligation (myocardial infarction size: 10.0 +/- 7.0% of left ventricular area in PDGF pretreatment [n=7] versus 17.6 +/- 5.6% in control [n=5] groups; P<0.03).

CONCLUSION:

Aging hearts have impaired angiogenic function as a result of depressed PDGF-B production. Restoration of the dysregulated endothelial PDGF-mediated angiogenic pathway in the aging heart reverses the senescent impairment in cardioprotective angiogenic function and offers a foundation for developing novel therapies for cardiovascular disease in older individuals.

• Authors: Jay M Edelberg, Seung H Lee, Manmeen Kaur, Lilong Tang, Nikki M Feirt, Samuel McCabe, Orville Bramwell, S Chiu Wong, Mun K Hong
• Journal: Circulation (Circulation) Vol. 105 Issue 5 Pg. 608-13 (Feb 05 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 11827927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• platelet-derived growth factor A
• platelet-derived growth factor AB

Topics

• Age Factors
• Aging (physiology)
• Animals
• Animals, Newborn
• Cells, Cultured
• Coculture Techniques
• Coronary Vessels (drug effects)
• Disease Models, Animal
• Endothelium, Vascular (cytology, drug effects)
• Graft Survival (drug effects)
• Heart Transplantation
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (pathology, prevention & control)
• Myocardium (cytology, metabolism, pathology)
• Neovascularization, Physiologic (drug effects)
• Platelet-Derived Growth Factor (biosynthesis, genetics, pharmacology)
• Proto-Oncogene Proteins c-sis (biosynthesis, genetics)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction