Calcium Signalling in Heart and Vessels: Role of Calmodulin and Downstream Calmodulin-Dependent Protein Kinases

Beghi, Sofia; Furmanik, Malgorzata; Jaminon, Armand M. G.; Veltrop, Rogier; Rapp, Nikolas; Wichapong, Kanin; Bidar, Elham; Buschini, Annamaria; Schurgers, Leon J.

doi:10.3390/ijms232416139

Cited by 19 publications

(9 citation statements)

References 169 publications

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“…Calmodulin 2 (CALM2), a signaling protein involved in the calcium-regulated contraction of cardiac muscle ( Beghi et al, 2022 ), was one of the most highly perturbed proteins in the heart proteome in this study. We examined the expression levels of CALM2 as well as an associated kinase (CAMKG2) via Western blots but did not see a statistical difference in abundance of either protein in the hearts of GCR 5-ion irradiated mice compared to unirradiated controls ( Supplementary Figures S2A, S3C ).…”

Section: Discussionmentioning

confidence: 94%

Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation

Kidane,

Lee,

Smith

et al. 2024

Front. Physiol.

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Introduction: It may take decades to develop cardiovascular dysfunction following exposure to high doses of ionizing radiation from medical therapy or from nuclear accidents. Since astronauts may be exposed continually to a complex space radiation environment unlike that experienced on Earth, it is unresolved whether there is a risk to cardiovascular health during long-term space exploration missions. Previously, we have described that mice exposed to a single dose of simplified Galactic Cosmic Ray (GCR5-ion) develop cardiovascular dysfunction by 12 months post-radiation.Methods: To investigate the biological basis of this dysfunction, here we performed a quantitative mass spectrometry-based proteomics analysis of heart tissue (proteome and phosphoproteome) and plasma (proteome only) from these mice at 8 months post-radiation.Results: Differentially expressed proteins (DEPs) for irradiated versus sham irradiated samples (fold-change ≥1.2 and an adjusted p-value of ≤0.05) were identified for each proteomics data set. For the heart proteome, there were 87 significant DEPs (11 upregulated and 76 downregulated); for the heart phosphoproteome, there were 60 significant differentially phosphorylated peptides (17 upregulated and 43 downregulated); and for the plasma proteome, there was only one upregulated protein. A Gene Set Enrichment Analysis (GSEA) technique that assesses canonical pathways from BIOCARTA, KEGG, PID, REACTOME, and WikiPathways revealed significant perturbation in pathways in each data set. For the heart proteome, 166 pathways were significantly altered (36 upregulated and 130 downregulated); for the plasma proteome, there were 73 pathways significantly altered (25 upregulated and 48 downregulated); and for the phosphoproteome, there were 223 pathways significantly affected at 0.1 adjusted p-value cutoff. Pathways related to inflammation were the most highly perturbed in the heart and plasma. In line with sustained inflammation, neutrophil extracellular traps (NETs) were demonstrated to be increased in GCR5-ion irradiated hearts at 12-month post irradiation. NETs play a fundamental role in combating bacterial pathogens, modulating inflammatory responses, inflicting damage on healthy tissues, and escalating vascular thrombosis.Discussion: These findings suggest that a single exposure to GCR5-ion results in long-lasting changes in the proteome and that these proteomic changes can potentiate acute and chronic health issues for astronauts, such as what we have previously described with late cardiac dysfunction in these mice.

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Section: Discussionmentioning

confidence: 94%

Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation

Kidane,

Lee,

Smith

et al. 2024

Front. Physiol.

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“…Furthermore, expression of these genes was significantly decreased upon RUNX1T1 knockdown (Figure 6B). Given the important role of Ca 2+ as an intracellular signal in skeletal muscle development and regeneration, 29 and the fact that CaM‐dependent kinases II (CAMKII), an important calcium signal transduction molecule, 30 is suppressed by RUNX1T1 depletion (Figure 6B), we investigated whether the calcium signaling pathway mediated the effect of RUNX1T1 on myogenic differentiation. Our results showed that the calcium ion content was elevated in the GPMs during myogenic differentiation (Figure 6C).…”

Section: Resultsmentioning

confidence: 99%

RUNX1T1 modulates myogenic differentiation by regulating the calcium signaling pathway and the alternative splicing of ROCK2

Deng

Liu

et al. 2023

The FASEB Journal

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RUNX1T1 (Runt-related transcription factor 1, translocated to 1) plays a wideranging and diverse role in cellular development, including hematopoiesis and adipogenesis. However, little is known about the function of RUNX1T1 in the skeletal muscle development. Here, we assessed the impact of RUNX1T1 on the proliferation and myogenic differentiation of goat primary myoblasts (GPMs). It was observed that RUNX1T1 is highly expressed during the early stages of myogenic differentiation and the fetal stage. Moreover, the knockdown of RUNX1T1 promotes the proliferation and inhibits myogenic differentiation and mitochondrial biogenesis of GPMs. RNA sequencing analysis revealed that significantly differentially expressed genes in RUNX1T1 knockdown cells were enriched in the calcium signaling pathway. Additionally, we discovered that RUNX1T1 regulates alternative splicing (AS) events involved in myogenesis. We also show that silencing RUNX1T1 blocked the Ca 2+ -CAMK signaling pathway and reduced the expression levels of muscle-specific isoforms of recombinant rho associated coiled coil containing crotein kinase 2 (ROCK2) during myogenic differentiation, partially explaining why RUNX1T1 deficiency leads to the impairment of myotube formation. These findings suggest that RUNX1T1 is a novel regulator of myogenic differentiation that regulates the calcium signaling pathway and AS of ROCK2. Overall, our results highlight the critical role of RUNX1T1 in myogenesis and broaden our understanding of myogenic differentiation.

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“…ABL1 participates in both the release of stored intracellular calcium and extracellular calcium entry [31]. CALM1 and CALM2 code for two isoforms of the calmodulin protein, which plays a crucial role in the contraction of vascular and cardiac tissue through the detection of intracellular calcium [32]. RYR2 is mainly expressed in cardiac tissue and codes for the main regulator of sarcoplasmic calcium release [33].…”

Section: Discussionmentioning

confidence: 99%

Differential expression analyses on aortic tissue reveal novel genes and pathways associated with abdominal aortic aneurysm onset and progression

Temprano-Sagrera,

Soto,

Dilmé

et al. 2024

Preprint

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Background: Abdominal aortic aneurysms (AAA) are focal dilatations of the abdominal aorta. They are normally asymptomatic and progressively expand, increasing their risk of rupture. Rupture of an AAA is associated with high mortality rates, but the mechanisms underlying the initiation, expansion and rupture of AAA are not yet fully understood. This study aims to characterize and identify new genes associated with the pathophysiology of AAA through differential expression analyses between dilated and non-dilated aortic tissue samples, and between AAA of different diameters. Our study used RNA-seq data on 140 samples, becoming the largest RNA-seq dataset for differential expression studies of AAA. Results: We identified 7,454 differentially expressed genes (DEGs) between AAA and controls, 2,851 of which were new compared to previous microarray studies. Notably, a novel cluster on adenosine triphosphate synthesis regulation emerged as strongly associated with AAA. Additionally, exploring AAA of different diameters identified eight genes (EXTL3, ZFR, DUSP8, DISP1, USP33, VPS37C, ZNF784, RFX1) that overlapped with the DEGs between AAA and controls, implying roles in both disease onset and progression. Seven genes (SPP1, FHL1, GNAS, MORF4L2, HMGN1, ARL1, RNASE4) with differential splicing patterns were also DEGs between AAA and controls, suggesting that splicing differences contribute to the observed expression changes and the disease development. Conclusions: This study identified new genes and pathways associated with AAA onset and progression and validated previous relevant roles of inflammation and intracellular calcium regulation. These findings provide insights into the complex mechanisms underlying AAA and indicate potential targets to limit AAA progression and mortality risk.

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Calcium Signalling in Heart and Vessels: Role of Calmodulin and Downstream Calmodulin-Dependent Protein Kinases

Cited by 19 publications

References 169 publications

Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation

Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation

RUNX1T1 modulates myogenic differentiation by regulating the calcium signaling pathway and the alternative splicing of ROCK2

Differential expression analyses on aortic tissue reveal novel genes and pathways associated with abdominal aortic aneurysm onset and progression

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