Insulin-like growth factor-1 overexpression in cardiomyocytes diminishes ex vivo heart functional recovery after acute ischemia.

Abstract

BACKGROUND:

Acute insulin-like growth factor-1 administration has been shown to have beneficial effects in cardiac pathological conditions. The aim of the present study was to assess the structural and ex vivo functional impacts of long-term cardiomyocyte-specific insulin-like growth factor-1 overexpression in hearts of transgenic αMHC-IGF-1 Ea mice.

METHODS:

Performance of isolated transgenic αMHC-IGF-1 Ea and littermate wild-type control hearts was compared under baseline conditions and in response to 20-min ischemic insult. Cardiac desmin and laminin expression patterns were determined histologically, and myocardial hydroxyproline was measured to assess collagen content.

RESULTS:

Overexpression of insulin-like growth factor-1 did not modify expression patterns of desmin or laminin but was associated with a pronounced increase (∼30%) in cardiac collagen content (from ∼3.7 to 4.8 μg/mg). Baseline myocardial contractile function and coronary flow were unaltered by insulin-like growth factor-1 overexpression. In contrast to prior evidence of acute cardiac protection, insulin-like growth factor-1 overexpression was associated with significant impairment of acute functional response to ischemia-reperfusion. Insulin-like growth factor-1 overexpression did not modify ischemic contracture development, but postischemic diastolic dysfunction was aggravated (51±5 vs. 22±6 mmHg in nontransgenic littermates). Compared with wild-type control, recovery of pressure development and relaxation indices relative to baseline performance were significantly reduced in transgenic αMHC-IGF-1 Ea after 60-min reperfusion (34±7% vs. 62±7% recovery of +dP/dt; 35±11% vs. 57±8% recovery of -dP/dt).

CONCLUSIONS:

Chronic insulin-like growth factor-1 overexpression is associated with reduced functional recovery after acute ischemic insult. Collagen deposition is elevated in transgenic αMHC-IGF-1 Ea hearts, but there is no change in expression of the myocardial structural proteins desmin and laminin. These findings suggest that sustained cardiac elevation of insulin-like growth factor-1 may not be beneficial in the setting of an acute ischemic insult.

• Authors: Cecilia M Prêle, Melissa E Reichelt, Steven E Mutsaers, Marilyn Davies, Lea M Delbridge, John P Headrick, Nadia Rosenthal, Marie A Bogoyevitch, Miranda D Grounds
• Journal: Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology (Cardiovasc Pathol) 2012 Jan-Feb Vol. 21 Issue 1 Pg. 17-27 ISSN: 1879-1336 [Electronic] United States
• PMID: 21266309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Desmin
• Laminin
• insulin-like growth factor-1, mouse
• Insulin-Like Growth Factor I
• Collagen

Topics

• Action Potentials
• Acute Disease
• Animals
• Biomarkers (metabolism)
• Blood Pressure (physiology)
• Collagen (metabolism)
• Coronary Circulation
• Desmin (metabolism)
• Disease Models, Animal
• Gene Expression
• Heart Rate (physiology)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Laminin (metabolism)
• Mice
• Mice, Transgenic
• Myocardial Contraction
• Myocardial Reperfusion Injury (metabolism, pathology, physiopathology)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Perfusion
• Recovery of Function