negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching
Definition
Target type: biologicalprocess
Any process that stops, prevents or reduces the frequency, rate or extent of vascular smooth muscle cell differentiation involved in phenotypic switching. [GO_REF:0000058, GOC:BHF, GOC:BHF_miRNA, GOC:rph, GOC:TermGenie, PMID:25089138]
Negative regulation of vascular associated smooth muscle cell differentiation, a crucial process in phenotypic switching, involves a complex interplay of signaling pathways, transcription factors, and epigenetic modifications. This process is characterized by a transition from a contractile, differentiated state to a synthetic, proliferative state. During this transition, smooth muscle cells (SMCs) lose their characteristic contractile proteins, such as smooth muscle α-actin and myosin, and gain the ability to synthesize extracellular matrix components, including collagen and elastin. This switch is driven by a variety of stimuli, including growth factors, cytokines, and mechanical stress.
One key mechanism of negative regulation is the suppression of the expression of genes involved in SMC differentiation. Transcription factors, such as myocardin and serum response factor (SRF), play a pivotal role in promoting SMC differentiation. Negative regulation can occur through the downregulation of these transcription factors or by the upregulation of their repressors.
Another important aspect is the modulation of signaling pathways. The transforming growth factor-beta (TGF-β) signaling pathway, for example, has been shown to play a significant role in promoting SMC differentiation. Conversely, the activation of the Ras/MAPK pathway, often stimulated by growth factors, has been associated with SMC dedifferentiation.
Epigenetic modifications, such as DNA methylation and histone acetylation, can also influence SMC differentiation. Hypermethylation of the promoters of SMC differentiation genes, for example, has been linked to reduced gene expression and a switch towards a synthetic phenotype.
In summary, negative regulation of vascular associated smooth muscle cell differentiation is a multi-faceted process involving the coordinated suppression of differentiation-promoting genes, activation of dedifferentiation pathways, and the modulation of epigenetic marks. These processes contribute to the phenotypic switching of SMCs, playing a critical role in vascular remodeling, atherosclerosis, and other vascular diseases.'
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Proteins (1)
| Protein | Definition | Taxonomy |
|---|---|---|
| DNA (cytosine-5)-methyltransferase 1 | A DNA (cytosine-5)-methyltransferase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P26358] | Homo sapiens (human) |
Compounds (21)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| procainamide | procainamide : A benzamide that is 4-aminobenzamide substituted on the amide N by a 2-(diethylamino)ethyl group. It is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias. Procainamide: A class Ia antiarrhythmic drug that is structurally-related to PROCAINE. | benzamides | anti-arrhythmia drug; platelet aggregation inhibitor; sodium channel blocker |
| vorinostat | vorinostat : A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL). Vorinostat: A hydroxamic acid and anilide derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used in the treatment of CUTANEOUS T-CELL LYMPHOMA and SEZARY SYNDROME. | dicarboxylic acid diamide; hydroxamic acid | antineoplastic agent; apoptosis inducer; EC 3.5.1.98 (histone deacetylase) inhibitor |
| dichlone | dichlone: structure | ||
| azacitidine | 5-azacytidine : An N-glycosyl-1,3,5-triazine that is 4-amino-1,3,5-triazin-2(1H)-one substituted by a beta-D-ribofuranosyl residue via an N-glycosidic linkage. An antineoplastic agent, it is used in the treatment of myeloid leukaemia. Azacitidine: A pyrimidine analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent. | N-glycosyl-1,3,5-triazine; nucleoside analogue | antineoplastic agent |
| epigallocatechin gallate | (-)-epigallocatechin 3-gallate : A gallate ester obtained by the formal condensation of gallic acid with the (3R)-hydroxy group of (-)-epigallocatechin. epigallocatechin gallate: a steroid 5alpha-reductase inhibitor and antimutagen in green tea (Camellia sinensis) | flavans; gallate ester; polyphenol | antineoplastic agent; antioxidant; apoptosis inducer; geroprotector; Hsp90 inhibitor; neuroprotective agent; plant metabolite |
| 5,5'-methylenedisalicylic acid | 5,5'-methylenedisalicylic acid: inhibits attachment of ribosomes to microsomal membranes; RN given refers to parent cpd; structure in first source & Merck Index, 9th ed, #5934 | ||
| s-tubercidinylhomocysteine | |||
| 6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene | 6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene: structure given in first source | monoterpenoid; organobromine compound; organochlorine compound | algal metabolite; antineoplastic agent; marine metabolite |
| s-adenosyl-3-thiopropylamine | S-adenosyl-3-thiopropylamine : A thioadenosine that is adenosine in which the hydroxy group at C-5' is replaced by a 3-aminopropyl group. S-adenosyl-3-thiopropylamine: decarboxylated S-adenosylhomocysteine; RN given refers to parent cpd | organic sulfide; primary amino compound; thioadenosine | |
| n(4)-adenosyl-n(4)-methyl-2,4-diaminobutanoic acid | |||
| nsc 401077 | NSC 401077: inhibits DNA methyltransferase DNMT1; structure in first source | ||
| s-adenosylhomocysteine | S-adenosyl-L-homocysteine : An organic sulfide that is the S-adenosyl derivative of L-homocysteine. S-Adenosylhomocysteine: 5'-S-(3-Amino-3-carboxypropyl)-5'-thioadenosine. Formed from S-adenosylmethionine after transmethylation reactions. | adenosines; amino acid zwitterion; homocysteine derivative; homocysteines; organic sulfide | cofactor; EC 2.1.1.72 [site-specific DNA-methyltransferase (adenine-specific)] inhibitor; EC 2.1.1.79 (cyclopropane-fatty-acyl-phospholipid synthase) inhibitor; epitope; fundamental metabolite |
| decitabine | 2'-deoxyribonucleoside | ||
| rg108 | RG108: DNA methyltransferase inhibitor; structure in first source | indolyl carboxylic acid | |
| genistein | 7-hydroxyisoflavones | antineoplastic agent; EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor; geroprotector; human urinary metabolite; phytoestrogen; plant metabolite; tyrosine kinase inhibitor | |
| psammaplin a | psammaplin A: isolated from marine sponges Poecillastra and Jaspis; structure in second source | ||
| sgi-1027 | SGI-1027: inhibits DNA methyltransferase 1; structure in first source | ||
| bix 01294 | piperidines | ||
| unc 0638 | UNC 0638: inhibits lysine methyltransferases G9a and GLP; structure in first source | quinazolines | |
| gsk343 | GSK343 : A member of the class of indazoles that is 1-isopropyl-1H-indazole-4-carboxamide in which the nitrogen of the carboxamide group is substituted by a (6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl group and in which the indazole ring is substituted at position 6 by a 2-(4-methylpiperazin-1-yl)pyridin-4-yl group. A highly potent and selective EZH2 inhibitor (IC50 = 4 nM). GSK343: an EZH2 methyltransferase inhibitor | aminopyridine; indazoles; N-alkylpiperazine; N-arylpiperazine; pyridone; secondary carboxamide | antineoplastic agent; apoptosis inducer; EC 2.1.1.43 (enhancer of zeste homolog 2) inhibitor |
| 6,7-dimethoxy-2-(pyrrolidin-1-yl)-n-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine | 6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine: a SETD8 inhibitor; structure in first source |