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1.
Circ Res ; 109(3): 272-80, 2011 Jul 22.
Article in English | MEDLINE | ID: mdl-21636802

ABSTRACT

RATIONALE: Paracrine growth factor-mediated crosstalk between cardiac myocytes and nonmyocytes in the heart is critical for programming adaptive cardiac hypertrophy in which myocyte size, capillary density, and the extracellular matrix function coordinately. OBJECTIVE: To examine the role that placental growth factor (PGF) plays in the heart as a paracrine regulator of cardiac adaptation to stress stimulation. METHODS AND RESULTS: PGF is induced in the heart after pressure-overload stimulation, where it is expressed in both myocytes and nonmyocytes. We generated cardiac-specific and adult inducible PGF-overexpressing transgenic mice and analyzed Pgf(-/-) mice to examine the role that this factor plays in cardiac disease and paracrine signaling. Although PGF transgenic mice did not have a baseline phenotype or a change in capillary density, they did exhibit a greater cardiac hypertrophic response, a greater increase in capillary density, and increased fibroblast content in the heart in response to pressure-overload stimulation. PGF transgenic mice showed a more adaptive type of cardiac growth that was protective against signs of failure with pressure overload and neuroendocrine stimulation. Antithetically, Pgf(-/-) mice rapidly died of heart failure within 1 week of pressure overload, they showed an inability to upregulate angiogenesis, and they showed significantly less fibroblast activity in the heart. Mechanistically, we show that PGF does not have a direct effect on cardiomyocytes but works through endothelial cells and fibroblasts by inducing capillary growth and fibroblast proliferation, which secondarily support greater cardiac hypertrophy through intermediate paracrine growth factors such as interleukin-6. CONCLUSIONS: PGF is a secreted factor that supports hypertrophy and cardiac function during pressure overload by affecting endothelial cells and fibroblasts that in turn stimulate and support the myocytes through additional paracrine factors.


Subject(s)
Cardiomegaly/metabolism , Cardiomegaly/physiopathology , Myocytes, Cardiac/physiology , Paracrine Communication/physiology , Pregnancy Proteins/metabolism , Adaptation, Physiological/physiology , Animals , Blood Pressure/physiology , Coronary Circulation/physiology , Endothelial Cells/physiology , Extracellular Matrix/physiology , Fibroblasts/physiology , Mice , Mice, Transgenic , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/physiopathology , Neovascularization, Physiologic/physiology , Placenta Growth Factor , Pregnancy Proteins/genetics , Stress, Physiological/physiology
2.
Nat Med ; 16(8): 872-9, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20639889

ABSTRACT

Hypertrophic heart disease is a leading health problem in Western countries. Here we identified the small EF hand domain-containing protein Ca(2+) and integrin-binding protein-1 (CIB1) in a screen for previously unknown regulators of cardiomyocyte hypertrophy. Yeast two-hybrid screening for CIB1-interacting partners identified a related EF hand domain-containing protein, calcineurin B, the regulatory subunit of the prohypertrophic protein phosphatase calcineurin. CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type Ca(2+) channel. CIB1 protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, Cib1-deleted mice showed a marked reduction in myocardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin-nuclear factor of activated T cells (NFAT) activity after pressure overload, whereas the degree of physiologic hypertrophy after swimming exercise was not altered. Transgenic mice with inducible and cardiac-specific overexpression of CIB1 showed enhanced cardiac hypertrophy in response to pressure overload or calcineurin signaling. Moreover, mice lacking Ppp3cb (encoding calcineurin A, beta isozyme) showed no enhancement in cardiac hypertrophy associated with CIB1 overexpression. Thus, CIB1 functions as a previously undescribed regulator of cardiac hypertrophy through its ability to regulate the association of calcineurin with the sarcolemma and its activation.


Subject(s)
Calcium-Binding Proteins/physiology , Cardiomegaly/genetics , Animals , Animals, Newborn , Calcineurin/metabolism , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Cardiomegaly/metabolism , Cardiomegaly/pathology , Cells, Cultured , Embryo, Mammalian , Heart/embryology , Heart/growth & development , Humans , Mice , Mice, Transgenic , Myocardium/metabolism , Myocardium/pathology , Protein Binding , Rats , Sarcolemma/metabolism
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