CIB1 Regulates Endothelial Cells and Ischemia-Induced Pathological and Adaptive Angiogenesis

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Circulation Research (Impact Factor: 11.09). 12/2007; 101(11):1185-93. DOI: 10.1161/CIRCRESAHA.107.157586
Source: PubMed

ABSTRACT Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. CIB1 (calcium- and integrin-binding protein), a 22-kDa EF-hand-containing protein, modulates the activity of p21-activated kinase 1 in fibroblasts. Because p21-activated kinase 1 also contributes to endothelial cell function, we hypothesized that CIB1 may have a role in angiogenesis. We found that endothelial cells depleted of CIB1 by either short hairpin RNA or homologous recombination have reduced migration, proliferation, and tubule formation. Moreover, loss of CIB1 in these cells decreases p21-activated kinase 1 activation, downstream extracellular signal-regulated kinase 1/2 activation, and matrix metalloproteinase 2 expression, all of which are known to contribute to angiogenesis. Consistent with these findings, tissues derived from CIB1-deficient (CIB1-/-) mice have reduced growth factor-induced microvessel sprouting in ex vivo organ cultures and in vivo Matrigel plugs. Furthermore, in response to ischemia, CIB1-/- mice demonstrate decreased pathological retinal and adaptive hindlimb angiogenesis. Ischemic CIB1-/- hindlimbs also demonstrate increased tissue damage and significantly reduced p21-activated kinase 1 activation. These data therefore reveal a critical role for CIB1 in ischemia-induced pathological and adaptive angiogenesis.

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Available from: Tina Leisner, Aug 11, 2015
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    • "It was further shown that CIB1-induced PAK1 activation is inhibitory to cell migration due to an LIM kinase-dependent increase in cofilin phosphorylation [Leisner et al., 2005]. However, the same group later showed that genetic ablation of CIB1 reduced endothelial cell migration on Fn and adhesion dependent PAK1 and Erk1/2 activation [Zayed et al., 2007]. Since PAK1 is also known to promote cell migration, it appears that PAK1 is able to regulate cell migration both positively and negatively [Ching et al., 2007; Huynh et al., 2010]. "
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    Journal of Cellular Biochemistry 11/2011; 112(11):3289-99. DOI:10.1002/jcb.23255 · 3.37 Impact Factor
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    • "These results suggest that pharmacological blocking of CIB1 could be a means to specifically suppress pathological cardiac hypertrophy. However, since CIB1 is expressed in a wide variety of tissues, CIB1 inhibitors likely would have to be cardiac-specific to circumvent side effects in other tissues such as impaired angiogenesis following ischemia, impaired thrombosis or male sterility, all of which were observed in Cib1 knockout mice (Naik et al., 2009; Yuan et al., 2006; Zayed et al., 2007). "
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    ABSTRACT: Ca(2+)-calcineurin-NFAT signaling plays a major role in promoting pathological cardiac hypertrophy. Heineke et al. (2010) show that CIB1 strongly enhances calcineurin activation and cardiac hypertrophy upon pathological stress, likely by functioning as a scaffold protein that exposes calcineurin to the L-Type Ca(2+) channel and the sarcolemma.
    Cell metabolism 09/2010; 12(3):205-6. DOI:10.1016/j.cmet.2010.08.007 · 16.75 Impact Factor
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    ABSTRACT: Platelet aggregation requires activation of the alphaIIbbeta3 integrin, an event regulated by the integrin cytoplasmic tails. CIB1 binds to the cytoplasmic tail of the integrin alphaIIb subunit. Previous over-expression and knockdown studies in murine megakaryocytes demonstrated that CIB1 inhibits integrin alphaIIbbeta3 activation. Here we analyzed Cib1(-/-) mice to determine the function of CIB1 in platelets in vitro and in vivo. We found that although these mice had no overt platelet phenotype, mRNA level of CIB1 homolog CIB3 was increased in Cib1(-/-) megakaryocytes. In vitro binding experiments showed that recombinant CIB1, -2 and -3 bound specifically to an alphaIIb cytoplasmic tail peptide. Subsequent protein modeling experiments indicated that CIBs 1-3 each have a highly conserved hydrophobic binding pocket. Therefore, the potential exists for compensation for the loss of CIB1 by these CIB family members, thereby preventing pathologic thrombus formation in Cib1(-/-) mice.
    Thrombosis and Haemostasis 12/2008; 100(5):847-56. DOI:10.1160/TH08-06-0351 · 5.76 Impact Factor
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