Journal Club
Pulmonary arterial hypertension and aging: Is there a connection?
Pulmonary arterial hypertension and cellular and molecular dimensions (13, 14). For aging: Is there a connection? example, “molecular aging” may be reflected by fact by Aleksandar Petrovic, Michael Seimetz, Argen Mamazhakypov, Oleg Pak, Akylbek Sydykov, Djuro Kosanovic
prelude Advanced age has been described as an important factor associated with various medical conditions, such as diabetes, kidney diseases, osteoporosis, arthritis, neurodegenerative disorders (Alzheimer´s and Parkinson´s diseases) and different cardiovascular alterations (atherosclerosis and hypertension) (1-3). In addition, available literature has indicated the existence of the “physiological aging of the respiratory system” and development of the lung parenchyma structural changes which may be characterized as emphysema-like (4). With regard to the pulmonary circulation, it has been revealed that pulmonary artery systolic pressure increased in healthy elders compared to the younger individuals, suggesting the presence of the “physiological aging of the pulmonary vascular system” (5-7). However, what does it mean for the development of pulmonary arterial hypertension (PAH)? Importantly, the recent intriguing findings postulated a clear shift from our previous point of view of PAH as a disease of younger females to a disease of older patients with no sharp difference in gender distribution (8-11). In order to identify and precisely delineate the potential role of aging in the pathology of pulmonary hypertension (PH), with the main focus on group 1 (12), we would like to start this interactive discussion among those interested in this topic. Our brief discussion will serve just to scratch the surface of this complex clinical and scientific issue.
Main Article Accumulated evidences from the scientific and clinical literature sources clearly indicated that the ultimate (and still unavoidable) effects of aging are “visible” at all levels of organism´s biology, starting from the whole body, organs and tissues up to the 17
that there is an accumulation of the reactive oxygen species (ROS) over time, which may lead to the subsequent ROS-induced damage of the essential macromolecules, such as DNA, proteins and lipids (14). At the cell level, it has been suggested that the cellular senescence represents an important event crucially associated with age (1, 13). Even more, this process is sometimes called as “cellular aging” (13). In general, the cellular senescence is defined as an event when the proliferating cells achieve the state of permanent cell-cycle arrest, and this phenomenon is characterized by a significant alteration in “normal” cell morphology, physiology and behavior (1, 13). Several different triggers apart from the historically known telomere shortening, including DNA damage, oncogene signals and oxidative stress, have been identified (1, 13). Despite these advances in the knowledge, it still remains unresolved how exactly the cellular senescence contributes to the development of age-related diseases. With regard to the cardiovascular disorders, it is known for a long time that these diseases, including atherosclerosis and hypertension, are associated with aging and such age-induced pathological events consider endothelial dysfunction, vascular remodeling and disorganized angiogenesis (1). The detailed description about the characteristics of endothelial (ECs) and vascular smooth muscle cell senescence and its potential connection with altered miRNA signaling in orchestrating the cardiovascular pathologies is nicely reviewed in the paper from Schraml and Grillari (1). Furthermore, an intriguing summary from Lakatta´s review article indicated enhancement of various signals and events which occur in humans over 65, such as pro-inflammatory and oxidative stress-related mediators (transforming growth factor-β, monocyte chemoattractant protein-1, nicotinamide adenine dinucleotide phosphate oxidase, tumor necrosis factor-α…),
Journal Club
Pulmonary arterial hypertension and aging: Is there a connection? matrix metalloproteinases and dysregulated cellular processes including endothelial dysfunction, intimal thickening, proliferation and migration (3). All people working in the field of pulmonary vascular research have already recognized that these signaling molecules and cellular events are also important players in development of pulmonary vascular remodeling and PAH (15-21).
(30).
Finally, focusing to the field of pulmonary vasculature and cellular senescence, some interesting findings have been demonstrated in the context of PH associated with chronic obstructive pulmonary disease (COPD), a lung disease known to be eo ipso age-dependent and characterized by telomere shortening (22, 23). The authors revealed that pulmonary artery smooth muscle cells (PASMCs) senescence is indeed a significant player in pulmonary vascular remodeling process, a hallmark of PH (22). Based on this knowledge, one can expect that senescent PASMCs may have similar properties and functions in development of PAH as compared to the lung disease associated PH, since many pathological events and features that underlie remodeling process are shared between different PH forms (24). Therefore, future research is crucially needed. Another interesting aspect is the potential involvement of dysregulated caveolae (invagination of the membrane, rich in cholesterol and sphingolipids) and its structural protein caveolin-1 in age-related cardiovascular pathologies, including PH/PAH (25-29). The contribution of caveolin-1 to the pathology of PAH is very complex story, and this protein actually may exert compartmentspecific opposite role in disease development and progression, dependent on the pulmonary vascular cell type involved (ECs versus PASMCs) (26-29). In the end, since the right heart failure is the ultimate pathological event of this severe pulmonary vascular disease, it is worth noting that aging healthy subjects and PAH patients show some similarities with regard to the right atrial function, compared to the younger healthy subjects and non-PAH controls, respectively
Is there a connection between pulmonary arterial hypertension and aging? Our question is directed to all scientists, clinicians and others interested in this topic across the world to try to answer and expose their own views, perspectives and visions in the next volume/issue of the PVRI Chronicle.
18
The question discussion
for
interactive
Based on the above described scientific and clinical facts, ideas and suggestions, we would like to postulate the following question:
References 1. Schraml E, Grillari J. From cellular senescence to age-associated diseases: the miRNA connection. Longevity & healthspan 2012; 1: 10. 2. Lakatta EG. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart failure reviews 2002; 7: 29-49. 3. Lakatta EG. So! What’s aging? Is cardiovascular aging a disease? Journal of molecular and cellular cardiology 2015; 83: 1-13. 4. Janssens JP, Pache JC, Nicod LP. Physiological changes in respiratory function associated with ageing. The European respiratory journal 1999; 13: 197-205. 5. Mahjoub H, Levy F, Cassol M, Meimoun P, Peltier M, Rusinaru D, Tribouilloy C. Effects of age on pulmonary artery systolic pressure at rest and during exercise in normal adults. European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology 2009; 10: 635-640. 6. Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ, Redfield MM. Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation 2009; 119: 26632670.
Journal Club
Pulmonary arterial hypertension and aging: Is there a connection?
7. Moreira EM, Gall H, Leening MJ, Lahousse L, Loth DW, Krijthe BP, Kiefte-de Jong JC, Brusselle GG, Hofman A, Stricker BH, Ghofrani HA, Franco OH, Felix JF. Prevalence of Pulmonary Hypertension in the General Population: The Rotterdam Study. PloS one 2015; 10: e0130072. 8. McGoon MD, Benza RL, Escribano-Subias P, Jiang X, Miller DP, Peacock AJ, Pepke-Zaba J, Pulido T, Rich S, Rosenkranz S, Suissa S, Humbert M. Pulmonary arterial hypertension: epidemiology and registries. Journal of the American College of Cardiology 2013; 62: D51-59. 9. Hoeper MM, Huscher D, Ghofrani HA, Delcroix M, Distler O, Schweiger C, Grunig E, Staehler G, Rosenkranz S, Halank M, Held M, Grohe C, Lange TJ, Behr J, Klose H, Wilkens H, Filusch A, Germann M, Ewert R, Seyfarth HJ, Olsson KM, Opitz CF, Gaine SP, Vizza CD, Vonk-Noordegraaf A, Kaemmerer H, Gibbs JS, Pittrow D. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. International journal of cardiology 2013; 168: 871-880. 10. Foley RJ, Wilcox D, Walsh SJ, Azrin M, Hager WD. Survival of geriatric idiopathic pulmonary arterial hypertension patients. Connecticut medicine 2011; 75: 11-15. 11. Lador F, Herve P. A practical approach of pulmonary hypertension in the elderly. Seminars in respiratory and critical care medicine 2013; 34: 654664. 12. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 2013; 62: D34-41. 13. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nature reviews Molecular cell biology 2007; 8: 729740. 14. Richardson AG, Schadt EE. The role of macromolecular damage in aging and age-related
disease. The journals of gerontology Series A, Biological sciences and medical sciences 2014; 69 Suppl 1: S28-32. 15. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nature reviews Cardiology 2011; 8: 443-455. 16. Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, Voelkel NF. Oxidative stress in severe pulmonary hypertension. American journal of respiratory and critical care medicine 2004; 169: 764-769. 17. Veit F, Pak O, Egemnazarov B, Roth M, Kosanovic D, Seimetz M, Sommer N, Ghofrani HA, Seeger W, Grimminger F, Brandes RP, Schermuly RT, Weissmann N. Function of NADPH oxidase 1 in pulmonary arterial smooth muscle cells after monocrotaline-induced pulmonary vascular remodeling. Antioxidants & redox signaling 2013; 19: 2213-2231. 18. Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, Reiss I, Ghofrani HA, Weissmann N, Kuebler WM, Seeger W, Grimminger F, Schermuly RT. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respiratory research 2011; 12: 60. 19. Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, Scheed A, Ritter C, Dahal BK, Vater A, Klussmann S, Ghofrani HA, Weissmann N, Klepetko W, Banat GA, Seeger W, Grimminger F, Schermuly RT. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. American journal of respiratory and critical care medicine 2012; 186: 897-908. 20. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, PepkeZaba J, Morrell NW. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122: 920-927. 19
Journal Club
Pulmonary arterial hypertension and aging: Is there a connection? 21. Chelladurai P, Seeger W, Pullamsetti SS. Matrix metalloproteinases and their inhibitors in pulmonary hypertension. The European respiratory journal 2012; 40: 766-782. 22. Noureddine H, Gary-Bobo G, Alifano M, Marcos E, Saker M, Vienney N, Amsellem V, Maitre B, Chaouat A, Chouaid C, Dubois-Rande JL, Damotte D, Adnot S. Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease. Circulation research 2011; 109: 543-553. 23. Savale L, Chaouat A, Bastuji-Garin S, Marcos E, Boyer L, Maitre B, Sarni M, Housset B, Weitzenblum E, Matrat M, Le Corvoisier P, Rideau D, Boczkowski J, Dubois-Rande JL, Chouaid C, Adnot S. Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine 2009; 179: 566-571. 24. Jain S, Ventura H, deBoisblanc B. Pathophysiology of pulmonary arterial hypertension. Seminars in cardiothoracic and vascular anesthesia 2007; 11: 104-109. 25. Fridolfsson HN, Patel HH. Caveolin and caveolae in age associated cardiovascular disease. Journal of geriatric cardiology : JGC 2013; 10: 6674. 26. Zhao YY, Liu Y, Stan RV, Fan L, Gu Y, Dalton N, Chu PH, Peterson K, Ross J, Jr., Chien KR. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proceedings of the National Academy of Sciences of the United States of America 2002; 99: 1137511380. 27. Zhao YY, Zhao YD, Mirza MK, Huang JH, Potula HH, Vogel SM, Brovkovych V, Yuan JX, Wharton J, Malik AB. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. The Journal of clinical
investigation 2009; 119: 2009-2018. 28. Mathew R. Cell-specific dual role of caveolin-1 in pulmonary hypertension. Pulmonary medicine 2011; 2011: 573432. 29. Patel HH, Zhang S, Murray F, Suda RY, Head BP, Yokoyama U, Swaney JS, Niesman IR, Schermuly RT, Pullamsetti SS, Thistlethwaite PA, Miyanohara A, Farquhar MG, Yuan JX, Insel PA. Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2007; 21: 2970-2979. 30. Willens HJ, Fertel DP, Qin J, Labrador E, Lowery MH. Effects of age and pulmonary arterial hypertension on the different phases of right atrial function. The international journal of cardiovascular imaging 2008; 24: 703-710. Corresponding Author
Djuro Kosanovic PhD Universities of Giessen and Marburg Lung Center (UGMLC) Excellence Cluster Cardio-Pulmonary System (ECCPS) German Center for Lung Research (DZL) ECCPS, Aulweg 130; 35392 Giessen; Germany +49 641 9946803 (Office); +49 641 9946839 (Fax) E-mail:
[email protected]
Aleksandar Petrovic(1) Michael Seimetz (1) Argen Mamazhakypov (1) Oleg Pak (1) Akylbek Sydykov (1) Djuro Kosanovic (1) (1) Universities of Giessen and Marburg Lung Center Excellence Cluster Cardio-Pulmonary System Member of the German Center for Lung Research ECCPS, Aulweg 130; 35392 Giessen; Germany
20
