Category — cardiovascular

Telomeres, the body’s own cellular clocks, may be a crucial factor underlying the development of emphysema, according to research from Johns Hopkins University.

“We found that in mice that have short telomeres, there was a significant increased risk of developing emphysema after exposure to cigarette smoke,” said Mary Armanios, MD, assistant professor of oncology at the Johns Hopkins School of Medicine.

The study appears online ahead of the print edition of the American Journal of Respiratory and Critical Care Medicine.

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Ramin Farzaneh-Far^1,2*, Jue Lin³, Elissa Epel⁴, Kyle Lapham³, Elizabeth Blackburn³, Mary A. Whooley^2,5,6

1 Division of Cardiology, San Francisco General Hospital, San Francisco, California, United States of America, 2 Department of Medicine, University of California San Francisco, San Francisco, California, United States of America, 3 Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America, 4 Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America, 5 Veterans Affairs Medical Center, San Francisco, California, United States of America, 6 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America

Christian Werner MD, Tobias Fürster MD, Thomas Widmann MD, Janine Pöss MD, Cristiana Roggia MD, Milad Hanhoun MD, Jürgen Scharhag MD, Nicole Büchner DBBSc, Tim Meyer MD, Wilfried Kindermann MD, Judith Haendeler PhD, Michael Böhm MD, and Ulrich Laufs MD

C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks. Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls.

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Kajstura J, Rota M, Urbanek K, Hosoda T, Bearzi C, Anversa P, Bolli R, Leri A. Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA.

The preservation of myocyte number and cardiac mass throughout life is dependent on the balance between cell death and cell division. Rapidly emerging evidence indicates that new myocytes can be formed through the activation and differentiation of resident cardiac progenitor cells. The critical issue is the identification of mechanisms that define the aging of cardiac progenitor cells and, ultimately, their inability to replace dying myocytes. The most reliable marker of cellular senescence is the modification of the telomere-telomerase axis, together with the expression of the cell cycle inhibitors p16INK4a and p53. Cellular senescence is characterized by biochemical events that occur within the cell. In this regard, one of the most relevant processes is represented by repeated oxidative stress that may evolve into the activation of the cell death program or result in the development of a senescent phenotype. Thus, the modulation of telomerase activity and the control of telomeric length, together with the attenuation of the formation of reactive oxygen species, may represent important therapeutic tools in regenerative medicine and in prevention of aging and diabetic cardiomyopathies.

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Minamino T, Komuro I.:Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. Front. Biosci. 1;13:2971-9.

Telomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal DNA-protein complexes that serve as protective caps for the chromosome ends. There is accumulating evidence that progressive telomere shortening is closely related to cardiovascular disease. For example, vascular cell senescence has been reported to occur in human atherosclerotic lesions and this change is associated with telomere shortening. Impairment of telomere integrity causes vascular dysfunction, which is prevented by the activation of telomerase. Mice with short telomeres develop hypertension and exhibit impaired neovascularization. Short telomeres have also been reported in the leukocytes of patients with cardiovascular disease or various cardiovascular risk factors. Although it remains unclear whether short telomeres directly cause cardiovascular disease, manipulation of telomere function is potentially an attractive strategy for the treatment of vascular senescence.

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Jose J. Fuster, Javier Diez and Vicente Andres. Journal of Hypertension, 25:2185-2192, 2007.

Aging is a major risk factor for hypertension and associated cardiovascular disease. In most proliferative tissues, aging is characterized by shortening of the DNA component of telomeres, the specialized genetic segments that cap the end of eukaryotic chromosomes and protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, telomere shortening is thought to contribute to organismal aging and to the development of age-related diseases. Here, we review animal and human studies that have investigated the possible links between telomere ablation and the pathogenesis of hypertension and related target organ damage. Although evidence is mounting that alterations in telomerase activity and telomere shortening may play a role in the pathogenesis of hypertension, additional studies are required to understand the molecular mechanisms by which telomere dysfunction and hypertension are functionally connected. As our knowledge on this emerging field grows, the challenge will be to ascertain whether all this information might translate into clinical applications.

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Annette L. Fitzpatrick, Richard A. Kronmal, Jeffrey P. Gardner, Bruce M. Psaty, Nancy S. Jenny, Russell P. Tracy, Jeremy Walston, Masyuki Kimura, and Abraham Aviv. American Journal of Epidemiology 2007; 165:14-21.

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age ¼ 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio ¼ 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio ¼ 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.

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Edwin Chang and Calvin B. Harley: Proc. Natl. Acad. Sci. USA Vol. 92, pp. 11190-11194, Cell Biology

Because repeated injury of the endothelium and subsequent turnover of intimal and medial cells have been implicated in atherosclerosis, we examined telomere length, a marker of somatic cell turnover, in cells from these tissues. Telomere lengths were assessed by Southern analysis of terminal restriction fragments (TRFs) generated by Hinfl/Rsa I digestion of human genomic DNA. Mean TRF length decreased as a function of population doublings in human endothelial cell cultures from umbilical veins, iliac arteries, and iliac veins. When endothelial cells were examined for mean TRF length as a function of donor age, there was a significantly greater rate of decrease for cells from iliac arteries than from iliac veins (102 bp/yr vs. 47 bp/yr, respectively, P < 0.05), consistent with higher hemodynamic stress and increased cell turnover in arteries. Moreover, the rate of telomere loss as a function of donor age was greater in the intimal DNA of iliac arteries compared to that of the internal thoracic arteries (147 bp/yr vs. 87 bp/yr, respectively, P < 0.05), a region of the arterial tree subject to less hemodynamic stress. This indicates that the effect is not tissue specific. DNA from the medial tissue of the iliac and internal thoracic arteries showed no significant difference in the rates of decrease, suggesting that chronic stress leading to cellular senescence is more pronounced in the intima than in the media. These observations extend the use of telomere size as a marker for the replicative history of cells and are consistent with a role for focal replicative senescence in cardiovascular diseases.

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Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Psychoneuroendocrinology. 2006 Apr;31(3):277-87.

We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres. Psychological stress is a major risk factor for cardiovascular disease (CVD), with multiple behavioral and physiological mediators. Telomere shortness has been associated with CVD, but the relationship between low telomerase activity, a potential precursor to telomere shortening, and CVD risk factors has not been examined in humans. Here we examine whether telomere length and telomerase in leukocytes are associated with physiological signs of stress arousal and CVD risk factors in 62 healthy women. Low telomerase activity in leukocytes was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine. Further, low telomerase activity was associated with the major risk factors for CVD -smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, greater abdominal adiposity-as well as to a composite Metabolic Syndrome variable. Telomere length was related only to elevated stress hormones (catecholamines and cortisol). Thus, we propose that low leukocyte telomerase constitutes an early marker of CVD risk, possibly preceding shortened telomeres, that results in part from chronic stress arousal. Possible cellular mechanisms by which low telomerase may link stress and traditional risk factors to CVD are discussed. These findings may implicate telomerase as a novel and important mediator of the effects of psychological stress on physical health and disease.

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