Tel: 1-631-626-9181 (USA)    44-207-097-1828 (Europe)
  Email:

ACTA2

Official Full Name
actin, alpha 2, smooth muscle, aorta
Background
The protein encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Defects in this gene cause aortic aneurysm familial thoracic type 6. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2008]
Synonyms
ACTA2; actin, alpha 2, smooth muscle, aorta; AAT6; ACTSA; MYMY5; actin, aortic smooth muscle; alpha-cardiac actin; cell growth-inhibiting gene 46 protein; alpha 2 actin; alpha-actin-2; growth-inhibiting gene 46; asma; alpha-actin; wu:fb63d03; sma

The ACTA2 (acetyl-CoA acetyltransferase 1) gene is located at 10q23.3, and the actin α encoded by it is the most abundant protein in mature vascular smooth muscle cells. Actin α accounts for 40% of total protein in vascular smooth muscle cells and 70% of total actin. The thin filaments composed of actin α periodically interact with the thick filaments to participate in the process of relaxation and contraction of blood vessels. Actin α is primarily involved in the contractile process. Thus, it is a marker protein of contractile vascular smooth muscle cells.

Studies have shown that vascular smooth muscle cells are transformed from the differentiated mature contractile phenotype to the dedifferentiated synthetic phenotype, accompanied by vascular smooth muscle cell migration and proliferation behavior, and the content of actin α and its recorded m RNA are significantly reduced. The transformation process of vascular smooth muscle cells from contractile phenotype to synthetic phenotype plays a very important role in coronary lesions. It is suggested that the study of ACTA2 gene is particularly important in the etiology of coronary artery disease.

ACTA2Figure 1. The relationship among smooth muscle actin, ACTA2 gene and contractile property in vasculopathies.(Yuan, et al. 2015)

Pathogenesis of ACTA2 and Thoracic Aortic Dissection

ACTA2 is the most common mutated gene in familial heritable thoracic aortic disease (FHTAD), accounting for about 14% of the total mutation. The ACTA2 gene encodes a smooth muscle cell(SMC), a specific subtype of SMC, α-actin, which is a key part of the smooth muscle cell contraction unit. Because about 40% of the protein in SMC contains SMC-specific α-actin. Guo et al. first used genome-wide linkage analysis and analysis of candidate genes to find that a missense mutation of the ACTA2 gene led to the substitution of R149C amino acid and led to FHTAD. Subsequently, an ACTA2 gene mutation was found in more non-thoracic aortic dissection (TAD) families. The pathogenic ACTA2 gene mutation is localized to p.R258C, which makes actin filaments more unstable and more susceptible to cleavage by cofilin. In addition, profilin binds more tightly to mutant actin, which may increase the binding of monomeric actin on SMC. In addition, myosin moves more slowly on mutant actin filaments. These studies have shown that mutant actin will reduce the ability of the SMC unit in the arterial wall to respond to arterial pulsations, which in turn causes abnormalities in the contraction of the aortic wall.

Clinically, patients with FHTAD secondary to the ACTA2 mutation have unique but not identical clinical features. In a study of 277 patients (41 ACTA2 mutations), the incidence of aortic degeneration (including dissection and aneurysm) at age 85 was 76%. However, mutations at two locations, p.R179 or p.R258, are at higher risk of causing adverse aortic events than at p.R185Q and p.R118Q. Aortic dissection accounts for 88% of aortic adverse events, and patients with type B aortic dissection have a lower age than patients with type A dissection. In patients with 1/3A aortic dissection, the diameter of the aorta is < 5 cm when the dissection occurs, indicating that the surgeon should consider surgery for patients with a mutation in the ACTA2 gene, even if the aortic diameter is < 5 cm. In addition to the increased risk of TAD, the ACTA2 gene mutation is associated with early-onset coronary artery disease and stroke.

Studies have shown that by pathological analysis of diseased blood vessels and in vitro culture of vascular smooth muscle cells, it is found that those who carry the ACTA2 mutation have a higher risk of vascular occlusion or vasodilatation,for example, early onset coronary heart disease, thoracic aortic dissection, thoracic aortic aneurysm, moyamoya disease, and ischemic stroke. Similar functional single nucleotide polymorphisms may be present in the promoter region of the ACTA2 gene in type 2 diabetes, which is directly or indirectly involved in the regulation of actin alpha transcription, thereby altering actin alpha content in vascular smooth muscle cells. And then modulate phenotypic transformation of vascular smooth muscle cells. Its accompanying vascular smooth muscle cell proliferation, migration, and other behaviors participate in the process of coronary artery disease. Therefore, these single nucleotide polymorphisms are likely to be associated with coronary artery disease in patients with type 2 diabetes.

References:

  1. Zhai, S., Zhao, M., Zhou, C., Lu, F., Zhang, H., & Li, N., et al. (2016). The association and significance of h3k27me3 and a folate metabolic gene acat2 in neural tube defects. Nutrition Journal, 15(1), 95.
  2. Lu, H., Fagnant, P. M., Bookwalter, C. S., Joel, P., & Trybus, K. M. (2015). Vascular disease-causing mutation r258c in acta2 disrupts actin dynamics and interaction with myosin. Proceedings of the National Academy of Sciences of the United States of America, 112(31), 4168-77.
  3. Hu, F. Y., Zheng, H. B., Xu, Y. M., Jiang, Y., Guo, H. Z., & Zhou, D. (2013). Acta2 is not a major responsible gene for spontaneous cerebral artery dissection. International Journal of Stroke, 8(6), E35-E35.
  4. Renard, M., Callewaert, B., & Baetens, M. (2013). Novel myh11 and acta2 mutations reveal a role for enhanced tgfβ signaling in ftaad. International Journal of Cardiology, 165(2), 314-321.
  5. Yuan, S. M. (2015). α-smooth muscle actin and acta2 gene expressions in vasculopathies:. Brazilian Journal of Cardiovascular Surgery, 30(6), 644-649.

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!