Ascending aortic aneurysm is a connective tissue disorder. Even though multiple novel gene mutations have been identified, risk profiling and diagnosis before rupture still represent a challenge. There are studies demonstrating shorter telomere lengths in the blood leukocytes of abdominal aortic aneurysm patients. The aim of this study was to measure whether relative telomere lengths are changed in the blood leukocytes of ascending aortic aneurysm patients. We also studied the expression of telomerase in aortic tissue samples of ascending aortic aneurysms. Relative lengths of leukocyte telomeres were determined from blood samples of patients with ascending aortic aneurysms and compared with healthy controls. Telomerase expression, both at the level of mRNA and protein, was quantified from the aortic tissue samples. Mean relative telomere length was significantly longer in ascending aortic aneurysm blood samples compared with controls (T/S ratio 0.87 vs. 0.61, p<0.001). Expressions of telomerase mRNA and protein were elevated in the aortic aneurysm samples (p<0.05 and p<0.01). Our study reveals a significant difference in the mean length of blood leukocyte telomeres in ascending aortic aneurysm and controls. Furthermore, expression of telomerase, the main compensating factor for telomere loss, is elevated at both the mRNA and protein level in the samples of aneurysmal aorta. Further studies will be needed to confirm if this change in telomere length can serve as a tool for assessing the risk of ascending aortic aneurysm.
References
[1]
Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, et al. (2006) Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 99: 156–164.
[2]
Zvereva MI, Shcherbakova DM, Dontsova OA (2010) Telomerase: structure, functions, and activity regulation. Biochemistry (Mosc) 75: 1563–1583.
[3]
Butt HZ, Atturu G, London NJ, Sayers RD, Bown MJ (2010) Telomere length dynamics in vascular disease: a review. Eur J Vasc Endovasc Surg 40: 17–26.
[4]
Elefteriades JA (2008) Thoracic aortic aneurysm: reading the enemy's playbook. Yale J Biol Med 81: 175–186.
[5]
Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, et al. (2009) Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet 84: 617–627.
[6]
Zhu L, Vranckx R, Khau Van Kien P, Lalande A, Boisset N, et al. (2006) Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 38: 343–349.
[7]
Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, et al. (2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355: 788–798.
[8]
Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, et al. (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36: 855–860.
[9]
van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, et al. (2011) Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 43: 121–126.
[10]
Atturu G, Brouilette S, Samani NJ, London NJ, Sayers RD, et al. (2010) Short leukocyte telomere length is associated with abdominal aortic aneurysm (AAA). Eur J Vasc Endovasc Surg 39: 559–564.
[11]
Balistreri CR, Pisano C, Merlo D, Fattouch K, Caruso M, et al. (2012) Is the mean blood leukocyte telomere length a predictor for sporadic thoracic aortic aneurysm? Data from a preliminary study. Rejuvenation Res 15: 170–173.
[12]
Wilson WR, Herbert KE, Mistry Y, Stevens SE, Patel HR, et al. (2008) Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease. Eur Heart J 29: 2689–2694.
[13]
Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30: e47.
[14]
Kakko S, Kelloniemi J, von Rohr P, Hoeschele I, Tamminen M, et al. (2003) ATP-binding cassette transporter A1 locus is not a major determinant of HDL-C levels in a population at high risk for coronary heart disease. Atherosclerosis 166: 285–290.
[15]
Huusko T, Salonurmi T, Taskinen P, Liinamaa J, Juvonen T, et al.. (2012) Elevated messenger RNA expression and plasma protein levels of osteopontin and matrix metalloproteinase types 2 and 9 in patients with ascending aortic aneurysms. J Thorac Cardiovasc Surg May 7.
[16]
Cafueri G, Parodi F, Pistorio A, Bertolotto M, Ventura F, et al. (2012) Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition. PLoS One 7: e35312.
[17]
Yan J, Yang Y, Chen C, Peng J, Ding H, et al. (2011) Short leukocyte telomere length is associated with aortic dissection. Intern Med 50: 2871–2875.
[18]
Blunder S, Messner B, Aschacher T, Zeller I, Turkcan A, et al. (2012) Characteristics of TAV- and BAV-associated thoracic aortic aneurysms–smooth muscle cell biology, expression profiling, and histological analyses. Atherosclerosis 220: 355–361.
[19]
Jondeau G, Boileau C (2012) Genetics of Thoracic Aortic Aneurysms. Curr Atheroscler Rep 14: 219–226.
[20]
Svenson U, Nordfjall K, Baird D, Roger L, Osterman P, et al. (2011) Blood cell telomere length is a dynamic feature. PLoS One 6: e21485.
[21]
Bischoff C, Petersen HC, Graakjaer J, Andersen-Ranberg K, Vaupel JW, et al. (2006) No association between telomere length and survival among the elderly and oldest old. Epidemiology 17: 190–194.
[22]
Martin-Ruiz CM, Gussekloo J, van Heemst D, von Zglinicki T, Westendorp RG (2005) Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study. Aging Cell 4: 287–290.
[23]
Hoffmann J, Erben Y, Zeiher AM, Dimmeler S, Spyridopoulos I (2009) Telomere length-heterogeneity among myeloid cells is a predictor for chronological ageing. Exp Gerontol 44: 363–366.
[24]
Spyridopoulos I, Erben Y, Brummendorf TH, Haendeler J, Dietz K, et al. (2008) Telomere gap between granulocytes and lymphocytes is a determinant for hematopoetic progenitor cell impairment in patients with previous myocardial infarction. Arterioscler Thromb Vasc Biol 28: 968–974.
[25]
Farzaneh-Far R, Cawthon RM, Na B, Browner WS, Schiller NB, et al. (2008) Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: data from the Heart and Soul Study. Arterioscler Thromb Vasc Biol 28: 1379–1384.
[26]
Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, et al. (2007) Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet 369: 107–114.
[27]
Gizard F, Heywood EB, Findeisen HM, Zhao Y, Jones KL, et al. (2011) Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages. Arterioscler Thromb Vasc Biol 31: 245–252.
[28]
Dimitroulis D, Katsargyris A, Klonaris C, Avgerinos ED, Fragou-Plemenou M, et al. (2011) Telomerase expression on aortic wall endothelial cells is attenuated in abdominal aortic aneurysms compared to healthy nonaneurysmal aortas. J Vasc Surg 54: 1778–1783.
[29]
Wiegreffe C, Christ B, Huang R, Scaal M (2009) Remodeling of aortic smooth muscle during avian embryonic development. Dev Dyn 238: 624–631.
[30]
Zarins CK, Xu C, Glagov S (2001) Atherosclerotic enlargement of the human abdominal aorta. Atherosclerosis 155: 157–164.
[31]
Haimovici H, Maier N (1964) Fate of Aortic Homografts in Canine Atherosclerosis. 3. Study of Fresh Abdominal and Thoracic Aortic Implants into Thoracic Aorta: Role of Tissue Susceptibility in Atherogenesis. Arch Surg 89: 961–969.
[32]
Ponnala S, Chetty C, Veeravalli KK, Dinh DH, Klopfenstein JD, et al. (2011) MMP-9 silencing regulates hTERT expression via beta1 integrin-mediated FAK signaling and induces senescence in glioma xenograft cells. Cell Signal 23: 2065–2075.
[33]
Findeisen HM, Gizard F, Zhao Y, Cohn D, Heywood EB, et al. (2011) Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol 31: 253–260.
[34]
Friedrich U, Griese E, Schwab M, Fritz P, Thon K, et al. (2000) Telomere length in different tissues of elderly patients. Mech Ageing Dev 119: 89–99.
