Key result
Inpp5f knockout mice showed augmented cardiac hypertrophy in response to stress compared to wild-type littermates, while cardiac overexpression of Inpp5f reduced hypertrophic responsiveness.
Inpp5f acts as a functionally important endogenous modulator of cardiac myocyte size and the cardiac response to stress.
Hypothesis-generating for Inpp5f as hypertrophy modulator; leaves open translation to human therapies.
RATIONALE: Cardiac hypertrophy occurs in response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway has previously been strongly associated with hypertrophic signaling in the heart, and with the control of cell size in multiple contexts. This pathway is tightly regulated by many factors, including a host of kinases and phosphatases that function at multiple steps in the signaling cascade. For example, the PTEN (phosphatase and tensin homolog) tumor suppressor protein is a phosphoinositide 3-phosphatase that, by metabolizing phosphatidylinositol 3,4,5-trisphosphate (PtdIns[3,4,5]P(3), PIP3), acts in direct antagonism to growth factor-stimulated PI3K. Inhibition of PTEN leads to cardiomyocyte hypertrophy. Another polyphoinositide phosphatase, inositol polyphosphate-5-phosphatase F (Inpp5f) has recently been implicated in regulation of cardiac hypertrophy. Like PTEN, this phosphatase can degrade PtdIns(3,4,5)P(3) and thus modulates the PI3K/Akt pathway. OBJECTIVE: To characterize the role of Inpp5f in regulating cardiac hypertrophy. METHODS AND RESULTS: We generated homozygous Inpp5f knockout mice and cardiac specific Inpp5f overexpression transgenic mice. We evaluated their hearts for biochemical, structural and functional changes. Inpp5f knockout mice have augmented hypertrophy and reactivation of the fetal gene program in response to stress when compared to wild-type littermates. Furthermore, cardiac overexpression of Inpp5f in transgenic mice reduces hypertrophic responsiveness. CONCLUSIONS: Our results suggest that Inpp5f is a functionally important endogenous modulator of cardiac myocyte size and of the cardiac response to stress.
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Zhu et al. (2009) studied Cardiac hypertrophy. Inpp5f knockout and cardiac specific Inpp5f overexpression vs. Wild-type littermates was evaluated on Biochemical, structural and functional changes (cardiac hypertrophy and reactivation of the fetal gene program in response to stress). Inpp5f knockout mice showed augmented cardiac hypertrophy in response to stress compared to wild-type littermates, while cardiac overexpression of Inpp5f reduced hypertrophic responsiveness.
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