A Shh coreceptor Cdo is required for efficient cardiomyogenesis of pluripotent stem cells

Dysregulation of Ca2+/calmodulin-dependent protein kinase (CaMK)II is closely linked with myocardial hypertrophy and heart failure. However, the mechanisms that regulate CaMKII activity are incompletely understood. Here we show that protein arginine methyltransferase 1 (PRMT1) is essential for preventing cardiac CaMKII hyperactivation. Mice null for cardiac PRMT1 exhibit a rapid progression to dilated cardiomyopathy and heart failure within 2 months, accompanied by cardiomyocyte hypertrophy and fibrosis. Consistently, PRMT1 is downregulated in heart failure patients. PRMT1 depletion in isolated cardiomyocytes evokes hypertrophic responses with elevated remodeling gene expression, while PRMT1 overexpression protects against pathological responses to neurohormones. The level of active CaMKII is significantly elevated in PRMT1-deficient hearts or cardiomyocytes. PRMT1 interacts with and methylates CaMKII at arginine residues 9 and 275, leading to its inhibition. Accordingly, pharmacological inhibition of CaMKII restores contractile function in PRMT1-deficient mice. Thus, our data suggest that PRMT1 is a critical regulator of CaMKII to maintain cardiac function.

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“…Immunostaining was carried out as previously described 53 . Briefly, cells were cultured on coverslip coated with gelatin.…”

Section: Methodsmentioning

confidence: 99%

“…Protein analysis was carried out as previously described 53 , 54 . Briefly, homogenized mouse hearts and cultured cells were lysed using RIPA buffer and analyzed by standard western blotting.…”

Section: Methodsmentioning

confidence: 99%

Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation

et al. 2018

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“…The Hedgehog (HH) signaling pathway coordinates embryonic and postnatal angiogenesis as well as organogenesis. In vertebrates, during the early embryonic development, HH morphogens play a crucial role in the development of organs such as limbs [ 6 , 7 ], neurons (axon elongation and astrocyte development) [ 8 , 9 , 10 ] and cardiac and vascular structures for septal cardiogenesis, angiogenesis and vasculogenesis [ 11 , 12 , 13 , 14 , 15 ]. Mammals have three genes with homology to the Hh gene, namely, Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH).…”

Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

Salybekov

Salybekova

Pola

et al. 2018

IJMS

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The Hedgehog (HH) signaling pathway plays an important role in embryonic and postnatal vascular development and in maintaining the homeostasis of organs. Under physiological conditions, Sonic Hedgehog (SHH), a secreted protein belonging to the HH family, regulates endothelial cell growth, promotes cell migration and stimulates the formation of new blood vessels. The present review highlights recent advances made in the field of SHH signaling in endothelial progenitor cells (EPCs). The canonical and non-canonical SHH signaling pathways in EPCs and endothelial cells (ECs) related to homeostasis, SHH signal transmission by extracellular vesicles (EVs) or exosomes containing single-strand non-coding miRNAs and impaired SHH signaling in cardiovascular diseases are discussed. As a promising therapeutic tool, the possibility of using the SHH signaling pathway for the activation of EPCs in patients suffering from cardiovascular diseases is further explored.

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“…The Hedgehog (Hh) signaling pathway has an essential biological function that orchestrates the development of embryonic, postnatal angiogenesis, and organogenesis. In an early embryological development of vertebrates Hh morphogen plays the crucial role on the development of organs such as limb [4,5], neuron (axon elongation, and astrocyte) [6][7][8], and cardiac and vascular (septal cardiogenesis, angiogenesis, and vasculogenesis) development [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

Salybekov¹,

Salybekova²,

Pola³

et al. 2018

Preprint

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A Shh coreceptor Cdo is required for efficient cardiomyogenesis of pluripotent stem cells

Cited by 17 publications

References 44 publications

Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation

Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation

Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

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