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CIB1 is a regulator of pathological cardiac hypertrophy.

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.

SUBMITTER: Heineke J

PROVIDER: S-EPMC2917617 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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CIB1 is a regulator of pathological cardiac hypertrophy.

Heineke Joerg J Auger-Messier Mannix M Correll Robert N RN Xu Jian J Benard Matthew J MJ Yuan Weiping W Drexler Helmut H Parise Leslie V LV Molkentin Jeffery D JD

Nature medicine 20100718 8

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 ...[more]

PMID: 20639889

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Project description:BackgroundPathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed.MethodsThe expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d.FindingsmiR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes.InterpretationOverexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy.FundingThis work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).

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CIB1 is a regulator of pathological cardiac hypertrophy.

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CIB1 is a regulator of pathological cardiac hypertrophy.

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