Cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signalling pathways dependent on extracellular calcium (Ca2+) influx that control normal and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the Ca2+ release-activated Ca2+ (CRAC) channel Orai1 and stromal interaction molecule 1 (Stim1) in postnatal cardiomycoyte store-operated Ca2+ entry (SOCE) and impact on normal and hypertrophic postnatal cardiomyocyte growth. Employing a combination of siRNA-mediated gene silencing, cultured neonatal rat ventricular cardiomyocytes together with indirect immunofluorescence, epifluorescent Ca2+ imaging and site-specific protein phosphorylation and real-time mRNA expression analysis, we show for the first time that both Orai1 and Stim1 are present in cardiomyocytes and required for SOCE due to intracellular Ca2+ store depletion by thapsigargin. Stim1-KD but not Orai1-KD significantly decreased diastolic Ca2+ levels and caffeine-releasable Ca2+ from the sarcoplasmic reticulum (SR). Conversely, Orai1-KD but not Stim1-KD significantly diminished basal NRCM cell size, anp and bnp mRNA levels and activity of the calcineurin (CnA) signaling pathway although diminishing both Orai1 and Stim1 protein similarly attenuated calmodulin kinase II (CamKII) and ERK1/2 activity under basal conditions. Both Orai1- and Stim1-KD completely abrogated phenylephrine (PE) mediated hypertrophic NRCM growth and enhanced natriuretic factor expression by inhibiting Gq-protein conveyed activation of the CaMKII and ERK1/2 signaling pathway. Interestingly, only Orai1-KD but not Stim1-KD prevented Gq-mediated CaN-dependent prohypertrophic signalling. This study shows for the first time that both Orai1 and Stim1 have a key role in cardiomyocyte SOCE regulating both normal and hypertrophic postnatal cardiac growth in vitro.
We report here 4 patients with restrictive dermopathy (RD) who presented in the paediatric and dermatology department of the University of Heidelberg from 1996 until 2017. All of the patients were premature infants displaying the pathognomonic clinical picture of RD: tense, vulnerable and translucent skin, superficial erosions, joint contractures, reduced motoricity and a typical facies with a small pinched nose, mouth fixed in an o-position, lowset ears and micrognathia (Fig. 1). Skin biopsies for light and electron microscopy showed collagen bundles parallel to the skin surface and a hypoplasia of appendages as common pathological findings. In 2 biopsies, the collagen fibres were small and in 3 of the 4 patients the rete ridges were flattened and elastic fibres were reduced or arranged in tiny clumps (Fig. 2b). All 4 babies developed respiratory insufficiency and died between days 6 and 32 after birth. (For more detailed information on each case see Table SI 1). RD has a pathognomonic phenotype; however, the underlying structural skin changes remain to be defined.
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