scholarly journals Length-independent telomere damage drives cardiomyocyte senescence

2018 ◽  
Author(s):  
Rhys Anderson ◽  
Anthony Lagnado ◽  
Damien Maggiorani ◽  
Anna Walaszczyk ◽  
Emily Dookun ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Dna Damage ◽  
Risk Factor ◽  
Cell Division ◽  
Cardiac Dysfunction ◽  
Cardiovascular Health ◽  
Myocardial Hypertrophy ◽  
Telomere Shortening ◽  
Age Related ◽  
Secretory Phenotype

AbstractAgeing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a and results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

P2255Senescence associated secretory phenotype exacerbates overload pressure-cardiac hypertrophy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D B Nugroho ◽  
K Ikeda ◽  
A Haryono ◽  
P Rinastiti ◽  
A J Barinda ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Conditioned Medium ◽  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Histological Analysis ◽  
Tissue Homeostasis ◽  
Heart Weight ◽  
Age Related ◽  
Secretory Phenotype

Abstract Background Advanced age is a significant risk factor for cardiovascular diseases such as hypertension and cardiac hypertrophy. The vascular system forms an essential component of cardiac tissue, to provide routes for circulation and transportation of nutrients and oxygen throughout the cardiac muscle. In addition to its function in vascular biology such as vasodilation and neovessel formation, endothelial cell (EC) also provides many secreted angiocrine factors that are crucially involved in maintaining tissue homeostasis. Ageing induces cellular senescence in various cells including EC. Senescent cells produce senescence-messaging secretomes that have deleterious effects on the tissue microenvironment, referred to as the senescence-associated secretory phenotype (SASP). Because of the crucial roles of EC in tissue homeostasis, EC senescence is presumed to play significant roles in age-related cardiac dysfunction, however, whether and the mechanism by which EC senescence affects age-related cardiac dysfunction remains to be elucidated. Purpose We aimed to investigate the role of senescent ECs in cardiac hypertrophy and heart function. Methods To investigate a contribution of senescent EC in age-related cardiac tissue dysfunction in vivo, we generated EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 (TRF2), which play a central role in the protection of chromosome ends, under the control of the vascular endothelial cadherin promoter (VEcad-TRF2DN-Tg). To induce pathological cardiac remodeling, Transverse Aortic Constriction (TAC) was performed in mice at the age of 10–12 weeks old. Cardiac function was assessed using fractional shortening percentage and ejection fraction measured with echocardiography every week until sacrifice day. Mice were sacrificed 4 weeks after TAC, heart tissue was collected for histological analysis, cardiac morphometry analysis, gene expression and protein expression analysis. In vitro, H9C2 rat cardiomyoblast cells were incubated with conditioned medium derived from control or senescent EC in the presence or absence of angiotensin II to induce cardiac hypertrophy. Results The serial echocardiographic analysis after TAC revealed the exacerbated LV dysfunction in VEcad-TRF2DN-Tg compared to that in wild-type mice. Morphometric and histological analysis 4 weeks after TAC showed increased heart weight and aggravated cardiac fibrosis in VEcad-TRF2DN-Tg mice. In vitro studies demonstrated that conditioned medium derived from senescent ECs enhanced cardiomyocyte hypertrophy in H9C2 cells. Of note, we found that treatment with Y2762, a Rho Kinase inhibitor, canceled the exacerbated cardiac hypertrophy caused by endothelial SASP. Conclusion These findings demonstrate for the first time that senescent ECs play causative roles in age-related cardiac disorders through the SASP, potentially by activating Rho-ROCK pathway in cardiomyocytes.

scholarly journals High Blood Pressure and Cardiovascular Disease

Hypertension ◽  
2020 ◽  
Vol 75 (2) ◽  
pp. 285-292 ◽  
Author(s):  
Flávio D. Fuchs ◽  
Paul K. Whelton
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Coronary Heart Disease ◽  
Risk Factor ◽  
Heart Disease ◽  
Cohort Studies ◽  
High Blood Pressure ◽  
Population Distribution ◽  
Meta Analysis ◽  
Age Related

Fragmented investigation has masked the overall picture for causes of cardiovascular disease (CVD). Among the risk factors for CVD, high blood pressure (BP) is associated with the strongest evidence for causation and it has a high prevalence of exposure. Biologically, normal levels of BP are considerably lower than what has typically been characterized as normal in research and clinical practice. We propose that CVD is primarily caused by a right-sided shift in the population distribution of BP. Our view that BP is the predominant risk factor for CVD is based on conceptual postulates that have been tested in observational investigations and clinical trials. Large cohort studies have demonstrated that high BP is an important risk factor for heart failure, atrial fibrillation, chronic kidney disease, heart valve diseases, aortic syndromes, and dementia, in addition to coronary heart disease and stroke. In multivariate modeling, the presumed attributable risk of high BP for stroke and coronary heart disease has increased steadily with progressive use of lower values for normal BP. Meta-analysis of BP-lowering randomized controlled trials has demonstrated a benefit which is almost identical to that predicted from BP risk relationships in cohort studies. Prevention of age-related increases in BP would, in large part, reduce the vascular consequences usually attributed to aging, and together with intensive treatment of established hypertension would eliminate a large proportion of the population burden of BP-related CVD.

scholarly journals Therapeutic Potential of Senolytics in Cardiovascular Disease

2020 ◽  
Author(s):  
Emily Dookun ◽  
João F. Passos ◽  
Helen M. Arthur ◽  
Gavin D. Richardson
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Cardiovascular Health ◽  
Therapeutic Potential ◽  
Senescent Cell ◽  
Apoptosis Induction ◽  
Secretory Phenotype ◽  
Artery Disease

Abstract Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the leading cause of death in 40% of individuals over 65 years old. Ageing is associated with both an increased prevalence of cardiovascular disease including heart failure, coronary artery disease, and myocardial infarction. Furthermore, ageing is associated with a poorer prognosis to these diseases. Genetic models allowing the elimination of senescent cells revealed that an accumulation of senescence contributes to the pathophysiology of cardiovascular ageing and promotes the progression of cardiovascular disease through the expression of a proinflammatory and profibrotic senescence-associated secretory phenotype. These studies have resulted in an effort to identify pharmacological therapeutics that enable the specific elimination of senescent cells through apoptosis induction. These senescent cell apoptosis-inducing compounds are termed senolytics and their potential to ameliorate age-associated cardiovascular disease is the focus of this review.

scholarly journals Senescence-associated extracellular vesicle release plays a role in senescence-associated secretory phenotype (SASP) in age-associated diseases

2020 ◽  
Author(s):  
Yoko Tanaka ◽  
Akiko Takahashi
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Extracellular Vesicle ◽  
The Body ◽  
Vesicle Release ◽  
Gene Pathway ◽  
Age Related ◽  
Suppression Mechanism ◽  
Inflammatory Proteins ◽  
Secretory Phenotype

Abstract Cellular senescence is an important tumour suppression mechanism that inhibits the proliferation of damaged cells. In senescent cells, irreparable DNA damage causes accumulation of genomic DNA fragments in the cytoplasm, which are recognized by the cyclic GMP-AMP synthase–stimulator of interferon gene pathway, resulting in secretion of numerous inflammatory proteins. This phenomenon is called senescence-associated secretory phenotype, and results in multiple physiological or pathological processes in the body. In addition, DNA damage also increases small extracellular vesicle release from senescent cells. This review presents recent insights into the molecular mechanisms and biological functions of senescence-associated extracellular vesicle release that is associated with age-related diseases, particularly cancer.

scholarly journals GH and Senescence: A New Understanding of Adult GH Action

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Vera Chesnokova ◽  
Shlomo Melmed
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Replicative Senescence ◽  
Aging Effects ◽  
Tissue Microenvironment ◽  
Senescent Phenotype ◽  
Age Related ◽  
Benign Nature ◽  
Secretory Phenotype ◽  
Somatic Copy Number Alterations

Abstract Replicative senescence occurs due to an inability to repair DNA damage and activation of p53/p21 and p16INK4 pathways. It is considered a preventive mechanism for arresting proliferation of DNA-damaged cells. Stably senescent cells are characterized by a senescence-associated secretory phenotype (SASP), which produces and secretes cytokines, chemokines, and/or matrix metalloproteinases depending on the cell type. SASP proteins may increase cell proliferation, facilitating conversion of premalignant to malignant tumor cells, triggering DNA damage, and altering the tissue microenvironment. Further, senescent cells accumulate with age, thereby aggravating age-related tissue damage. Here, we review a heretofore unappreciated role for growth hormone (GH) as a SASP component, acting in an autocrine and paracrine fashion. In senescent cells, GH is activated by DNA-damage-induced p53 and inhibits phosphorylation of DNA repair proteins ATM, Chk2, p53, and H2AX. Somatotroph adenomas containing abundant intracellular GH exhibit increased somatic copy number alterations, indicative of DNA damage, and are associated with induced p53/p21. As this pathway restrains proliferation of DNA-damaged cells, these mechanisms may underlie the senescent phenotype and benign nature of slowly proliferating pituitary somatotroph adenomas. In highly proliferative cells, such as colon epithelial cells, GH induced in response to DNA damage suppresses p53, thereby triggering senescent cell proliferation. As senescent cells harbor unrepaired DNA damage, GH may enable senescent cells to evade senescence and reenter the cell cycle, resulting in acquisition of harmful mutations. These mechanisms, at least in part, may underlie pro-aging effects of GH observed in animal models and in patients with chronically elevated GH levels.

scholarly journals A DNA Damage Response-Independent Mechanism for Telomere Shortening-Elicited Age-Related Pathologies

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 885-885
Author(s):  
Amanda Stock ◽  
Kun Wang ◽  
Chongkui Sun ◽  
Chengyu Liu ◽  
Yi Gong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Transcription ◽  
Dna Damage Response ◽  
Cell Fractionation ◽  
Telomeric Dna ◽  
Independent Manner ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Age Related ◽  
Damage Response

Abstract Telomere attrition is associated with telomeropathies and age-related pathologies. In telomeropathies, telomere uncapping induces a DNA damage response (DDR) that drives apoptosis or senescence. However, a defined mechanism by which telomere attrition contributes to other age-related pathologies has not been determined. Telomere integrity is maintained by shelterin, a six-protein complex. Rap1 is the only shelterin member that is not essential for telomere capping but engages non-telomeric DNA and regulates gene transcription. We hypothesized that non-telomeric Rap1 accumulation could contribute to age-related pathologies in a DDR-independent manner. To test this, we used CRISPR/Cas9 editing to generate a Rap1 mutant mouse model in which Rap1 at telomeres is prevented, leaving only non-telomeric Rap1. Indirect immunostaining showed no differences in telomere dysfunction-induced DDR foci in Rap1 mutant compared to wild-type primary fibroblasts. Cell fractionation/western blotting of fibroblasts from Rap1 mutants demonstrated decreased Rap1 expression and Rap1 re-localization off telomeres, which mimics the same alteration of Rap1 in human cells with telomere attrition. Rap1 mutant mice exhibited increased body weight and altered metabolic and immune-response transcripts in various tissues, indicating that altered transcription could account for some of the observed phenotypes related to telomere attrition. In conclusion, telomere shortening may facilitate non-telomeric Rap1, which alters gene transcription and drives metabolic and immune dysfunction in a DDR-independent manner.

scholarly journals Sleep‐Disordered Breathing and Cardiovascular Disease in Children and Adolescents

2021 ◽  
Vol 10 (18) ◽  
Author(s):  
Carissa M. Baker‐Smith ◽  
Amal Isaiah ◽  
Maria Cecilia Melendres ◽  
Joseph Mahgerefteh ◽  
Anayansi Lasso‐Pirot ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Risk Factor ◽  
Sleep Apnea ◽  
Children And Adolescents ◽  
Sleep Disordered Breathing ◽  
Cardiovascular Health ◽  
Systemic Hypertension ◽  
Scientific Statement ◽  
The Impact ◽  
Disordered Breathing

Abstract Obstructive sleep apnea (OSA) is a known risk factor for cardiovascular disease in adults. It is associated with incident systemic hypertension, arrhythmia, stroke, coronary artery disease, and heart failure. OSA is common in children and adolescents, but there has been less focus on OSA as a primary risk factor for cardiovascular disease in children and adolescents. This scientific statement summarizes what is known regarding the impact of sleep‐disordered breathing and, in particular, OSA on the cardiovascular health of children and adolescents. This statement highlights what is known regarding the impact of OSA on the risk for hypertension, arrhythmia, abnormal ventricular morphology, impaired ventricular contractility, and elevated right heart pressure among children and adolescents. This scientific statement also summarizes current best practices for the diagnosis and evaluation of cardiovascular disease–related complications of OSA in children and adolescents with sleep apnea and highlights potential future research in the area of sleep‐disordered breathing and cardiovascular health during childhood and adolescence.

B-Vitamins, Methylenetetrahydrofolate Reductase (MTHFR) and Hypertension

2011 ◽  
Vol 81 (4) ◽  
pp. 240-244 ◽  
Author(s):  
Mary Ward ◽  
Carol P Wilson ◽  
J J Strain ◽  
Geraldine Horigan ◽  
John M. Scott ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Risk Factor ◽  
Low Dose ◽  
Methylenetetrahydrofolate Reductase ◽  
Genetic Determinant ◽  
Gene Encoding ◽  
Homocysteine Concentration ◽  
Homozygous Mutant ◽  
B Vitamin

Hypertension is a leading risk factor for cardiovascular disease (CVD) and stroke. A common polymorphism in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR), previously identified as the main genetic determinant of elevated homocysteine concentration and also recognized as a risk factor for CVD, appears to be independently associated with hypertension. The B-vitamin riboflavin is required as a cofactor by MTHFR and recent evidence suggests it may have a role in modulating blood pressure, specifically in those with the homozygous mutant MTHFR 677 TT genotype. If studies confirm that this genetic predisposition to hypertension is correctable by low-dose riboflavin, the findings could have important implications for the management of hypertension given that the frequency of this polymorphism ranges from 3 to 32 % worldwide.

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