Abstract:Key Words: Scpep1 Ⅲ smooth muscle Ⅲ neointima Ⅲ protease Ⅲ knockout S mooth muscle cells (SMCs) are critical for blood vessel homeostasis, but they also contribute to the pathogenesis of several vasculopathies. In response to arterial injury, SMCs shift from a quiescent, contractile phenotype to a proliferative, synthetic state that undermines normal arterial function leading to neointimal formation. 1,2 Myriad factors and cytokines, as well as proteases and their associated substrates, have been implicated in… Show more
“…SCPEP1 gene was originally identified in rat aortic smooth muscle cells by screening for retinoid-inducible genes (Chen et al 2001). Lee et al (2009) study demonstrates a role for SCPEP1 activity in modulating smooth muscle proliferation, migration and vascular remodelling. Nothing is known about SCPEP1 gene and function on skeletal muscle but further studies are needed to clarify the role of this serine carboxypeptidase in this specific tissue.…”
Genome-wide association study results are presented for intramuscular fat in Italian Large White pig breed. A total of 886 individuals were genotyped with PorcineSNP60 BeadChip. After quality control performed with plink software and in R environment, 49 208 markers remained for the association analysis. The genome-wide association studies was conducted using linear mixed model implemented in GenABEL. We detected seven new SNPs of genes till now not found associated to intramuscular fat (IMF). Three markers map in a wide intergenic region rich of QTL linked to fat traits, one map 388 kb upstream the gene SDK1, one map inside PPP3CA gene, one inside SCPEP1 gene and the last is not mapped in the porcine genome yet. Associations here presented indicate a moderate effect of these genes on IMF. In particular, PPP3CA, that is involved in the oxidative metabolism of skeletal muscle, could be considerated as an interesting candidate gene for IMF content in pigs. However, further studies are needed to clarify the role of these genes on the physiological processes involved in IMF regulation. These results may be useful to control this trait that is important in terms of nutritional, technological and organoleptic characteristics of fresh meat and processed products.
“…SCPEP1 gene was originally identified in rat aortic smooth muscle cells by screening for retinoid-inducible genes (Chen et al 2001). Lee et al (2009) study demonstrates a role for SCPEP1 activity in modulating smooth muscle proliferation, migration and vascular remodelling. Nothing is known about SCPEP1 gene and function on skeletal muscle but further studies are needed to clarify the role of this serine carboxypeptidase in this specific tissue.…”
Genome-wide association study results are presented for intramuscular fat in Italian Large White pig breed. A total of 886 individuals were genotyped with PorcineSNP60 BeadChip. After quality control performed with plink software and in R environment, 49 208 markers remained for the association analysis. The genome-wide association studies was conducted using linear mixed model implemented in GenABEL. We detected seven new SNPs of genes till now not found associated to intramuscular fat (IMF). Three markers map in a wide intergenic region rich of QTL linked to fat traits, one map 388 kb upstream the gene SDK1, one map inside PPP3CA gene, one inside SCPEP1 gene and the last is not mapped in the porcine genome yet. Associations here presented indicate a moderate effect of these genes on IMF. In particular, PPP3CA, that is involved in the oxidative metabolism of skeletal muscle, could be considerated as an interesting candidate gene for IMF content in pigs. However, further studies are needed to clarify the role of these genes on the physiological processes involved in IMF regulation. These results may be useful to control this trait that is important in terms of nutritional, technological and organoleptic characteristics of fresh meat and processed products.
“…Later study by Lee at al. [27] reported that the Scpep1 -null mice generated by replacing exons 1 and 2 of the Scpep1 gene with Neo cassette show a decrease in medial and intimal cell proliferation as well as in vessel remodelling following arterial injury. The same study also reported that a ∼50% knockdown of endogenous Scpep1 in mouse ASMC line showed dramatic decrease in serum-stimulated growth.…”
The potent vasoconstrictor peptides, endothelin 1 (ET-1) and angiotensin II control adaptation of blood vessels to fluctuations of blood pressure. Previously we have shown that the circulating level of ET-1 is regulated through its proteolytic cleavage by secreted serine carboxypeptidase, cathepsin A (CathA). However, genetically-modified mouse expressing catalytically inactive CathA S190A mutant retained about 10–15% of the carboxypeptidase activity against ET-1 in its tissues suggesting a presence of parallel/redundant catabolic pathway(s). In the current work we provide direct evidence that the enzyme, which complements CathA action towards ET-1 is a retinoid-inducible lysosomal serine carboxypeptidase 1 (Scpep1), a CathA homolog with previously unknown biological function. We generated a mouse strain devoid of both CathA and Scpep1 activities (DD mice) and found that in response to high-salt diet and systemic injections of ET-1 these animals showed significantly increased blood pressure as compared to wild type mice or those with single deficiencies of CathA or Scpep1. We also found that the reactivity of mesenteric arteries from DD mice towards ET-1 was significantly higher than that for all other groups of mice. The DD mice had a reduced degradation rate of ET-1 in the blood whereas their cultured arterial vascular smooth muscle cells showed increased ET-1-dependent phosphorylation of myosin light chain 2. Together, our results define the biological role of mammalian serine carboxypeptidase Scpep1 and suggest that Scpep1 and CathA together participate in the control of ET-1 regulation of vascular tone and hemodynamics.
“…Despite extensive surveying and testing, there are no known substrates for SCPEP1 making this protein an “orphan protease”. Genetic inactivation of SCPEP1 does not show an overt phenotype as mice survive and breed without any histological evidence of pathology[109],[110]. However, upon ligation injury of the carotid artery, SCPEP1 null mice show reduced neointimal load suggesting that SCPEP1 directs VSMC migration and proliferation.…”
Section: Retinoids and Vsmc Phenotypementioning
confidence: 99%
“…However, upon ligation injury of the carotid artery, SCPEP1 null mice show reduced neointimal load suggesting that SCPEP1 directs VSMC migration and proliferation. Indeed, adenoviral delivery of SCPEP1 to VSMC causes accelerated growth and migration in a catalytic triad-dependent manner[110]. Interestingly, SCPEP1 is secreted from cells in a non cleaved manner though it is not clear as yet whether extracellular SCPEP1 exhibits biological activity.…”
Vascular smooth muscle cells have attracted considerable interest as a model for a flexible program of gene expression. This cell type arises throughout the embryo body plan via poorly understood signaling cascades that direct the expression of transcription factors and microRNAs which, in turn, orchestrate the activation of contractile genes collectively defining this cell lineage. The discovery of myocardin and its close association with serum response factor has represented a major break-through for the molecular understanding of vascular smooth muscle cell differentiation. Retinoids have been shown to improve the outcome of vessel wall remodeling following injury and have provided further insights into the molecular circuitry that defines the vascular smooth muscle cell phenotype. This review summarizes the progress to date in each of these areas of vascular smooth muscle cell biology.
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