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  1. Afroz R, Cao Y, Rostam MA, Ta H, Xu S, Zheng W, et al.
    Pharmacol Ther, 2018 07;187:88-97.
    PMID: 29454855 DOI: 10.1016/j.pharmthera.2018.02.005
    Atherosclerosis commences with the trapping of low density lipoproteins (LDLs) in blood vessels by modified proteoglycans (PGs) with hyperelongated glycosaminoglycan (GAG) chains. GAG chain synthesis and growth factor mediated hyperelongation regulates the composition and size of PGs in a manner that would cause low density lipoprotein (LDLs) retention in vessel wall. Galactosaminoglycans are a class of GAGs, commonly observed on PGs. Multiple enzymes are involved in galactosaminoglycan biosynthesis. Galactosaminoglycan synthesis is regulated by various signalling pathways which are amenable to pharmacological manipulation to treat atherosclerosis. Receptor mediated signalling pathways including protein tyrosine kinase receptors (PTKRs), serine/threonine kinase receptors (S/TKRs) and G-protein coupled receptors (GPCRs) pathways regulate galactosaminoglycan synthesizing enzyme expression. Increased expression of these enzymes modify galactosaminoglycan chain structure by making them hyperelongated. This review focuses on the signalling pathways regulating the expression of genes involved in galactosaminoglycan synthesis and modification. Furthermore, there are multiple other processes for inhibiting the interactions between LDL and galactosaminoglycans such as peptide mimetics of ApoB100 and anti-galactosaminoglycan antibodies and the therapeutic potential of these strategies is also addressed.
    Matched MeSH terms: Muscle, Smooth, Vascular/metabolism*
  2. Loh YC, Tan CS, Ch'ng YS, Ahmad M, Asmawi MZ, Yam MF
    Molecules, 2016 Apr 15;21(4):495.
    PMID: 27092479 DOI: 10.3390/molecules21040495
    This paper is a review on the types of antagonists and the signaling mechanism pathways that have been used to determine the mechanisms of action employed for vasodilation by test compounds. Thus, we exhaustively reviewed and analyzed reports related to this topic published in PubMed between the years of 2010 till 2015. The aim of this paperis to suggest the most appropriate type of antagonists that correspond to receptors that would be involved during the mechanistic studies, as well as the latest signaling pathways trends that are being studied in order to determine the route(s) that atest compound employs for inducing vasodilation. The methods to perform the mechanism studies were included. Fundamentally, the affinity, specificity and selectivity of the antagonists to their receptors or enzymes were clearly elaborated as well as the solubility and reversibility. All the signaling pathways on the mechanisms of action involved in the vascular tone regulation have been well described in previous review articles. However, the most appropriate antagonists that should be utilized have never been suggested and elaborated before, hence the reason for this review.
    Matched MeSH terms: Muscle, Smooth, Vascular/metabolism
  3. Loong BJ, Tan JH, Lim KH, Mbaki Y, Ting KN
    Naunyn Schmiedebergs Arch Pharmacol, 2015 Oct;388(10):1061-7.
    PMID: 26051407 DOI: 10.1007/s00210-015-1140-3
    The functional responses of different overnight-stored in vitro tissues are not clearly described in any animal model. The influence of overnight storage in an animal model may vary between tissue types. We employed Sprague-Dawley rat as our animal model and investigated the functional changes of rat aorta, trachea, bronchus and bladder that were used (i) immediately after surgical removal (denoted as fresh) and (ii) after storage in aerated (95% O2, 5% CO2) Krebs-Ringer bicarbonate solution at 4 °C for 24 h (denoted as stored). The aorta ring was pre-contracted with phenylephrine, and the functional response of the tissue was investigated using isoprenaline, forskolin and carbachol. Carbachol was also used to increase the tone in trachea, bronchus rings and bladder strips. A clear reduced function of endothelium, with a minor if any effect in the smooth muscle function in rat aorta was observed after overnight storage. The contractile response of overnight-stored rat airway (trachea and bronchus) and bladder smooth muscles remained unchanged. Among all tested tissues, only bronchus showed a reduced response rate (only 40% responded) after storage. In vitro rat tissues that are stored in Krebs solution at 4 °C for 24 h can still be used to investigate smooth muscle responses, however, not endothelium-mediated responses for aorta. The influence of overnight storage on different tissues from an animal model (Sprague-Dawley rat in our study) also provides an insight in maximising the use of sacrificed animals.
    Matched MeSH terms: Muscle, Smooth, Vascular/metabolism
  4. Nguyen DDN, Zain SM, Kamarulzaman MH, Low TY, Chilian WM, Pan Y, et al.
    Am J Physiol Heart Circ Physiol, 2021 10 01;321(4):H770-H783.
    PMID: 34506226 DOI: 10.1152/ajpheart.00058.2021
    Vascular aging is highly associated with cardiovascular morbidity and mortality. Although the senescence of vascular smooth muscle cells (VSMCs) has been well established as a major contributor to vascular aging, intracellular and exosomal microRNA (miRNA) signaling pathways in senescent VSMCs have not been fully elucidated. This study aimed to identify the differential expression of intracellular and exosomal miRNA in human VSMCs (hVSMCs) during replicative senescence. To achieve this aim, intracellular and exosomal miRNAs were isolated from hVSMCs and subsequently subjected to whole genome small RNA next-generation sequencing, bioinformatics analyses, and qPCR validation. Three significant findings were obtained. First, senescent hVSMC-derived exosomes tended to cluster together during replicative senescence and the molecular weight of the exosomal protein tumor susceptibility gene 101 (TSG-101) increased relative to the intracellular TSG-101, suggesting potential posttranslational modifications of exosomal TSG-101. Second, there was a significant decrease in both intracellular and exosomal hsa-miR-155-5p expression [n = 3, false discovery rate (FDR) < 0.05], potentially being a cell type-specific biomarker of hVSMCs during replicative senescence. Importantly, hsa-miR-155-5p was found to associate with cell-cycle arrest and elevated oxidative stress. Lastly, miRNAs from the intracellular pool, that is, hsa-miR-664a-3p, hsa-miR-664a-5p, hsa-miR-664b-3p, hsa-miR-4485-3p, hsa-miR-10527-5p, and hsa-miR-12136, and that from the exosomal pool, that is, hsa-miR-7704, were upregulated in hVSMCs during replicative senescence (n = 3, FDR < 0.05). Interestingly, these novel upregulated miRNAs were not functionally well annotated in hVSMCs to date. In conclusion, hVSMC-specific miRNA expression profiles during replicative senescence potentially provide valuable insights into the signaling pathways leading to vascular aging.NEW & NOTEWORTHY This is the first study on intracellular and exosomal miRNA profiling on human vascular smooth muscle cells during replicative senescence. Specific dysregulated sets of miRNAs were identified from human vascular smooth muscle cells. Hsa-miR-155-5p was significantly downregulated in both intracellular and exosomal hVSMCs, suggesting its crucial role in cellular senescence. Hsa-miR-155-5p might be the mediator in linking cellular senescence to vascular aging and atherosclerosis.
    Matched MeSH terms: Muscle, Smooth, Vascular/metabolism*
  5. Mokhtar SS, Vanhoutte PM, Leung SW, Suppian R, Yusof MI, Rasool AH
    Eur J Pharmacol, 2016 Feb 15;773:78-84.
    PMID: 26825543 DOI: 10.1016/j.ejphar.2016.01.013
    Diabetes is associated with endothelial dysfunction, which is characterized by impaired endothelium-dependent relaxations. The present study aimed to examine the role of nitric oxide (NO), prostacyclin and endothelium-dependent hyperpolarization (EDH), in the relaxation of ventral tail arteries of rats under diabetic conditions. Relaxations of tail arteries of control and diabetic rats were studied in wire myograph. Western blotting and immunostaining were used to determine the presence of proteins. Acetylcholine-induced relaxations were significantly smaller in arteries of diabetic compared to control rats (Rmax; 70.81 ± 2.48% versus 85.05 ± 3.15%). Incubation with the combination of non-selective cyclooxygenase (COX) inhibitor, indomethacin and potassium channel blockers, TRAM 34 and UCL 1684, demonstrated that NO-mediated relaxation was attenuated significantly in diabetic compared to control rats (Rmax; 48.47 ± 5.84% versus 68.39 ± 6.34%). EDH-type (in the presence of indomethacin and NO synthase inhibitor, LNAME) and prostacyclin-mediated (in the presence of LNAME plus TRAM 34 and UCL 1684) relaxations were not significantly reduced in arteries of diabetic compared to control rats [Rmax: (EDH; 17.81 ± 6.74% versus 34.16 ± 4.59%) (prostacyclin; 15.85 ± 3.27% versus 17.23 ± 3.75%)]. Endothelium-independent relaxations to sodium nitroprusside, salbutamol and prostacyclin were comparable in the two types of preparations. Western blotting and immunostaining indicated that diabetes diminished the expression of endothelial NO synthase (eNOS), while increasing those of COX-1 and COX-2. Thus, since acetylcholine-induced NO-mediated relaxation was impaired in diabetes because of reduced eNOS protein expression, pharmacological intervention improving NO bioavailability could be useful in the management of diabetic endothelial dysfunction.
    Matched MeSH terms: Muscle, Smooth, Vascular/metabolism
  6. Yu EPK, Reinhold J, Yu H, Starks L, Uryga AK, Foote K, et al.
    Arterioscler Thromb Vasc Biol, 2017 12;37(12):2322-2332.
    PMID: 28970293 DOI: 10.1161/ATVBAHA.117.310042
    OBJECTIVE: Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis.

    APPROACH AND RESULTS: Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis.

    CONCLUSIONS: Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.

    Matched MeSH terms: Muscle, Smooth, Vascular/metabolism*
  7. Kimura TE, Duggirala A, Hindmarch CC, Hewer RC, Cui MZ, Newby AC, et al.
    J Mol Cell Cardiol, 2014 Jul;72(100):9-19.
    PMID: 24534707 DOI: 10.1016/j.yjmcc.2014.02.001
    AIMS: Cyclic AMP inhibits vascular smooth muscle cell (VSMC) proliferation which is important in the aetiology of numerous vascular diseases. The anti-mitogenic properties of cAMP in VSMC are dependent on activation of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), but the mechanisms are unclear.

    METHODS AND RESULTS: Selective agonists of PKA and EPAC synergistically inhibited Egr1 expression, which was essential for VSMC proliferation. Forskolin, adenosine, A2B receptor agonist BAY60-6583 and Cicaprost also inhibited Egr1 expression in VSMC but not in endothelial cells. Inhibition of Egr1 by cAMP was independent of cAMP response element binding protein (CREB) activity but dependent on inhibition of serum response element (SRE) activity. SRF binding to the Egr1 promoter was not modulated by cAMP stimulation. However, Egr1 expression was dependent on the SRF co-factors Elk1 and 4 but independent of MAL. Inhibition of SRE-dependent Egr1 expression was due to synergistic inhibition of Rac1 activity by PKA and EPAC, resulting in rapid cytoskeleton remodelling and nuclear export of ERK1/2. This was associated with de-phosphorylation of the SRF co-factor Elk1.

    CONCLUSION: cAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. This occurs, at least in part, via inhibition of Rac1 activity leading to rapid actin-cytoskeleton remodelling, nuclear export of ERK1/2, impaired Elk1-phosphorylation and inhibition of SRE activity. This identifies one of the earliest mechanisms underlying the anti-mitogenic effects of cAMP in VSMC but not in endothelial cells, making it an attractive target for selective inhibition of VSMC proliferation.

    Matched MeSH terms: Muscle, Smooth, Vascular/metabolism
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