Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice.
To test the hypothesis that early interventional treatment with insulin-like growth factor-1 (IGF-1) alleviates subsequent development of dilated cardiomyopathy, cardiac-specific IGF-1 expression was introduced by selective cross-breeding into a transgenic mouse model of heart failure that displays phenotypic characteristics of severe dilation. Hemodynamic, structural, and cellular parameters of the heart were compared between nontransgenic, tropomodulin-overexpressing cardiomyopathic, and the hybrid tropomodulin/IGF-1-overexpressing mice. Beneficial effects of IGF-1 were apparent by multiple indices of cardiac structure and function, including normalization of heart mass, anatomy, hemodynamics, and apoptosis. IGF-1 expression also acted as a proliferative stimulus as evidenced by calculated increases in myocyte number as well as expression of Ki67, a nuclear marker of cellular replication. Cellular analyses revealed that IGF-1 inhibited characteristic cardiomyocyte elongation in dilated hearts and restored calcium dynamics comparable to that observed in normal cells. Collectively, these results provide novel information regarding the ability of IGF-1 to inhibit progression of cardiomyopathic disease in a defined model system and suggest that heart failure may benefit from early interventional IGF-1 treatment.
Welch
Sara
S
Divisions of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Plank
David
D
Witt
Sandra
S
Glascock
Betty
B
Schaefer
Erik
E
Chimenti
Stefano
S
Andreoli
Anna Maria
AM
Limana
Federica
F
Leri
Annarosa
A
Kajstura
Jan
J
Anversa
Piero
P
Sussman
Mark A
MA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002452:Cell Count; D048429:Cell Size; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D051348:Tropomodulin; D020257:Ventricular Remodeling / Q000235:genetics
D002352:Carrier Proteins; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; C495831:Tmod1 protein, mouse; D051348:Tropomodulin; D007334:Insulin-Like Growth Factor I; D002118:Calcium