Premium
Conditional Overexpression of Cardiac‐Specific PI3Kα Improves Basal Myocardial Function
Author(s) -
Yano Naohiro,
Zhao Ting C,
Tseng Andy,
Padbury James F,
Tseng YiTang
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.966.6
Subject(s) - pi3k/akt/mtor pathway , genetically modified mouse , cardiac function curve , transgene , basal (medicine) , biology , medicine , endocrinology , protein kinase b , andrology , microbiology and biotechnology , signal transduction , heart failure , gene , biochemistry , insulin
We have shown that PI3K signaling is highly regulated during cardiac development with the highest levels found during the fetal‐neonatal transition period and the lowest in adult. Transgenic models have established overexpression of the PI3K signaling results in increased organ size. The effects on proliferation, however, have not been carefully examined in vivo . To study the effects of PI3K on cardiomyocyte proliferation, we have engineered a tet‐off conditional transgenic mouse model to control the overexpression of cardiac‐specific PI3Kα. Newborn and adult transgenic mice were allowed to overexpress PI3Kα for two weeks and cell proliferation and basal myocardial functions were assessed, respectively. Basal cardiac function was assessed with the Langendorff perfusion system. Cell proliferation was measured with Ki‐67/troponin T double‐labeling immunohistochemistry. Overexpression of cardiac PI3Kα, Akt and p70S6K was confirmed and was associated with an increase in cyclin D1 but not cyclin D3 levels. Adult transgenic mice had better myocardial performance including LV developed pressure, LV dP/dt max and LV dP/dt min. Heart rate and heart/body weight ratio were not changed. Overexpression of PI3Kα was also associated with an increase in cardiomyocyte proliferation in newborns. Hence, cardiac PI3K signaling can be conditionally overexpressed in postnatal stages when there is normally very limited PI3K activity. The new transgenic model can be used to investigate the mechanisms underlying regulation of cardiomyocyte proliferation during development and cardiac remodeling following injury. (NIH 1 P20 RR018728 )