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Title: LOCAL INSULIN-LIKE GROWTH FACTOR I EXPRESSION INDUCES PHYSIOLOGIC, THEN PATHOLOGIC CARDIAC HYPERTROPHY IN TRANSGENIC MICE

Author
item DELAUGHTER, M - BAYLOR COLLEGE OF MED
item TAFFET, GEORGE - BAYLOR COLLEGE OF MED
item Fiorotto, Marta
item ENTMAN, MARK - BAYLOR COLLEGE OF MED
item Schwartz, Robert

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/19/1999
Publication Date: N/A
Citation: Delaughter, M.C., Taffet, G.E., Fiorotto, M.L., Entman, M.L., Schwartz, R.J. 1999. Local insulin-like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice. Journal of Federation of American Societies for Experimental Biology. 13(14):1923-1929.

Interpretive Summary: Cardiac hypertrophy, which refers to heart enlargement, is a risk factor for serious heart problems. Insulin-like growth factor I (IGF-I) is an amino acid peptide hormone produced in response to growth hormone stimulation. On one hand, IGF-I has been implicated as a primary factor in the development of cardiac hypertrophy under pressure overload, but on the other hand, IGF-I has been under consideration as a potential therapeutic treatment because it has been shown to improve cardiac performance after heart failure. Because of these conflicting observations, we wanted to determine the nature of the long-term effects of IGF-I on heart function. In this study, we report that persistent expression of IGF-I in a transgenic mouse model, initially induced benefits in terms of an improvement in heart contractions, but later in life, the continued exposure to IGF-I resulted in compromised heart function, manifested by undesirable changes in the heart cells, reduced contractions, and increase fibrosis. These findings raise questions about this hormone's use as a therapy over the long term in treating cardiovascular disease. Thus, this report makes an important contribution to doctors' understanding of an important hormone and its effects on heart function and disease.

Technical Abstract: In the present study we determined the long-term effects of persistent, local Insulin-like Growth Factor I (IGF-I) expression on cardiac function in the SIS2 transgenic mouse. Cardiac mass/body mass was increased in SIS2 mice by 10 weeks of age; this cardiac hypertrophy became more pronounced later in life. Peak aortic outflow velocity, a correlate of cardiac output, was increased at 10 weeks in SIS2 mice, but was decreased at 52 weeks in SIS2 mice. 72 week SIS2 mouse hearts exhibited wide variability in the extent of cardiac hypertrophy and the area of individual cardiac myofibers was enlarged. Sirius Red staining revealed increased fibrosis in 72 week SIS2 hearts. In conclusion, persistent local IGF-I expression is sufficient to induce initially an analog of physiologic cardiac hypertrophy. However, this hypertrophy progresses to a pathologic condition characterized by decreased systolic performance and increased fibrosis. Our results confirm the short-term systolic performance benefit of increased systemic IGF-I, but our demonstration that IGF-I ultimately diminishes systolic performance raises doubt about the therapeutic value of chronic IGF-I administration. Considering these findings, limiting temporal exposure to IGF-I seems the most likely means of delivering IGF- I's potential benefits while avoiding its deleterious side-effects.