Despite the significant advances in the profound understanding of the disease pathobiology and identification of the potential therapeutic approaches/strategies during the last decade, pulmonary hypertension (PH) in all its forms still remains enigmatic and represents a noticeable health burden for one hundred million patients worldwide1,2. Obesity, a medical condition often recognized to be associated with different adverse cardiovascular consequences regardless of the existence of the “obesity paradox”, is increasingly prevalent in the modern age, especially in the developed world3-5. Although the recent literature implicates the potential role of obesity in the development of PH and indicates adiponectin as a potential molecular link, the research in this direction is still in its dawn and requires future studies6, 7. Considering this, we would like to hypothesize that a plethora of different molecular mediators/signals mostly related to altered inflammation and augmented oxidative stress may represent a pathological bridge between the obese condition and PH. This interactive discussion aims to mobilize scientists and other persons interested in the field to express their perspectives in order to identify new potential molecular links shared amongst severe pulmonary vascular disease and obesity.
Adiponectin, a protein exclusively synthesized by adipose tissue, is found to be reduced in the obese condition (Figure 1) and its deficiency alters the vascular homeostasis in the lungs with promotion of pulmonary vascular disease development3,8. Furthermore, the literature demonstrates that over-expression of this anti-inflammatory adipokine is associated with attenuation of the pulmonary vascular remodeling in animal models of PH, in response to inflammatory and hypoxic stimuli7,9,10. Therefore, adiponectin may represent a potential molecular link between the obese condition and PH, and its protective role for the pulmonary vasculature is strongly indicative7,11. In addition to adiponectin, we would like to point out that a plethora of different molecular signals/mediators may be potentially shared between PH and increased adipose tissue/ obesity (Figure 1). In the context of obesity and its cardiovascular consequences, Musaad and Haynes systematically reviewed a variety of bioactive molecules mostly focusing on altered inflammation and enhanced oxidative stress, as two major mechanisms suggested to be involved in the cardiovascular pathology associated with the obese condition3 . It is worth mentioning that both pathological events, such as augmented inflammation and oxidative stress, are also important culprits in the pathogenesis of PH12-14. Increased adipose tissue and obesity lead to elevation in the levels of interleukin-6 (IL-6), tumor necrosis factor alpha(TNF-α), monocyte chemoattractant protein-1 (MCP-1), angiotensinogen (Ang), F2 isoprostanes (F2 IsoPs), C-reactive protein (CRP), fibrinogen, resistin, serum amyloid A, oxidized low density lipoprotein (oxLDL) and homocysteine (for details, see the review article from Musaad and Haynes)3 . Resistin is another adipose tissue-derived candidate, in addition to adiponectin, with visible properties to be associated with pathologies of both obesity and PH3,15,16. In particular, resistin induces the proliferation of the human smooth muscle cells via activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase signaling pathways, and promotes the proliferation and migration of human endothelial cells, suggesting the potential involvement of this adipose tissue-derived molecule in pulmonary vascular remodeling15,16.
IL-6 is a cytokine which dysregulates the normal proliferation and apoptosis of the pulmonary arterial smooth muscle cells and endothelial cells, and therefore represents an important player in the pathogenesis of pulmonary arterial hypertension (PAH)17. TNF-α is a cytokine which is also involved in the pathology of PH, and TNF-α antagonism exerts beneficial therapeutic effects in the monocrotaline model of PAH18. MCP-1, a pro-inflammatory chemokine, is increased in the plasma of idiopathic PAH (IPAH) patients. Additionally, its plasma level correlates with the disease severity in patients with chronic thromboembolic PH (CTEPH), clearly suggesting this chemokine as a potential player in the pathology of PH19,20. Furthermore, a therapeutic blockade of the MCP-1 signaling results in the attenuation of the experimental PH21. Considering the above, and knowing that IL-6, TNF-α and MCP-1 are also augmented in obesity, it is tempting to speculate that these three pro-inflammatory mediators may represent a potential pathological bridge between PH and obesity3 . Ang levels are increased in obesity, and in the context of PH the role of angiotensin system is as previously described, thereby indicating another potential link between these two medical conditions3,22,23. Enhanced oxidative stress is indeed an important pathological feature in both PH and obesity, and some biomarkers for oxidative stress, such as oxLDL and F2 IsoPs, may further illuminate the search for the common themes among the pulmonary vascular disease and obesity3,12,24-27.
Finally, the available literature indicates additional molecular signals/mediators which are suggested to be increased in the obese condition, as potential biomarkers and/or active players in the pathology of different clinical forms of PH, such as homocysteine, fibrinogen, serum amyloid A and CRP3,28-32. In detail, augmented levels of:
1) homocysteine are found in patients suffering from PAH associated with congenital heart disease, as well as in IPAH patients28,29;
2) serum amyloid A are demonstrated in the patients with sickle cell disease complicated with PH30;
3) fibrinogen Aα in CTEPH patients31; and
4) circulating CRP in both CTEPH and PAH forms32.
The question for interactive discussion
We would like to postulate the following question to the scientific community worldwide:
What else except adiponectin may represent a molecular link between PH and obesity?
All experts and other persons interested in the field are welcome to reply and express their views on this topic, in the next volume of PVRI Chronicle.
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2. Simonneau, G., Gatzoulis, M.A., Adatia, I., Celermajer, D., Denton, C., Ghofrani, A., Gomez Sanchez, M.A., Krishna Kumar, R., Landzberg, M., Machado, R.F., et al. 2013. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34-41.
3. Musaad, S., and Haynes, E.N. 2007. Biomarkers of obesity and subsequent cardiovascular events. Epidemiol Rev 29:98-114.
4. Mathew, B., Francis, L., Kayalar, A., and Cone, J. 2008. Obesity: effects on cardiovascular disease and its diagnosis. J Am Board Fam Med 21:562-568.
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7. Summer, R., Walsh, K., and Medoff, B.D. 2011. Obesity and pulmonary arterial hypertension: Is adiponectin the molecular link between these conditions? Pulm Circ 1:440- 447.
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9. Ouchi, N., and Walsh, K. 2008. A novel role for adiponectin in the regulation of inflammation. Arterioscler Thromb Vasc Biol 28:1219-1221.
10. Weng, M., Raher, M.J., Leyton, P., Combs, T.P., Scherer, P.E., Bloch, K.D., and Medoff, B.D. 2011. Adiponectin decreases pulmonary arterial remodeling in murine models of pulmonary hypertension. Am J Respir Cell Mol Biol 45:340-347.
11. Hansmann, G., and Rabinovitch, M. 2010. The protective role of adiponectin in pulmonary vascular disease. Am J Physiol Lung Cell Mol Physiol 298:L1-2.
12. Bowers, R., Cool, C., Murphy, R.C., Tuder, R.M., Hopken, M.W., Flores, S.C., and Voelkel, N.F. 2004. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med 169:764-769.
13. Dahal, B.K., Kosanovic, D., Kaulen, C., Cornitescu, T., Savai, R., Hoffmann, J., Reiss, I., Ghofrani, H.A., Weissmann, N., Kuebler, W.M., et al. 2011. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res 12:60.
14. Savai, R., Pullamsetti, S.S., Kolbe, J., Bieniek, E., Voswinckel, R., Fink, L., Scheed, A., Ritter, C., Dahal, B.K., Vater, A., et al. 2012. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 186:897-908.
15. Calabro, P., Samudio, I., Willerson, J.T., and Yeh, E.T. 2004. Resistin promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation 110:3335-3340.
16. Mu, H., Ohashi, R., Yan, S., Chai, H., Yang, H., Lin, P., Yao, Q., and Chen, C. 2006. Adipokine resistin promotes in vitro angiogenesis of human endothelial cells. CardiovascRes 70:146-157.
17. Furuya, Y., Satoh, T., and Kuwana, M. 2010. Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol 2010:720305.
18. Wang, Q., Zuo, X.R., Wang, Y.Y., Xie, W.P., Wang, H., and Zhang, M. 2013. Monocrotaline-induced pulmonary arterial hypertension is attenuated by TNF-alpha antagonists via the suppression of TNF-alpha expression and NF-kappaB pathway in rats. Vascul Pharmacol 58:71-77.
19. Itoh, T., Nagaya, N., Ishibashi-Ueda, H., Kyotani, S., Oya, H., Sakamaki, F., Kimura, H., and Nakanishi, N. 2006. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology 11:158-163.
20. Kimura, H., Okada, O., Tanabe, N., Tanaka, Y., Terai, M., Takiguchi, Y., Masuda, M., Nakajima, N., Hiroshima, K., Inadera, H., et al. 2001. Plasma monocyte chemoattractant protein-1 and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 164:319-324.
21. Ikeda, Y., Yonemitsu, Y., Kataoka, C., Kitamoto, S., Yamaoka, T., Nishida, K., Takeshita, A., Egashira, K., and Sueishi, K. 2002. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 283:H2021-2028.
22. Morrell, N.W., Morris, K.G., and Stenmark, K.R. 1995. Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension. Am J Physiol 269:H1186-1194.
23. Jeffery, T.K., and Wanstall, J.C. 1999. Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function. Br J Pharmacol 128:1407- 1418.
24. Janssen, L.J. 2008. Isoprostanes and lung vascular pathology. Am J Respir Cell Mol Biol 39:383-389.
25. Dromparis, P., and Michelakis, E.D. 2012. F2-isoprostanes: an emerging pulmonary arterial hypertension biomarker and potential link to the metabolic theory of pulmonary arterial hypertension? Chest 142:816-820.
26. Cracowski, J.L., Degano, B., Chabot, F., Labarere, J., Schwedhelm, E., Monneret, D., Iuliano, L., Schwebel, C., Chaouat, A., Reynaud-Gaubert, M., et al. 2012. Independent association of urinary F2-isoprostanes with survival in pulmonary arterial hypertension. Chest 142:869-876.
27. Ogura, S., Shimosawa, T., Mu, S., Sonobe, T., Kawakami-Mori, F., Wang, H., Uetake, Y., Yoshida, K., Yatomi, Y., Shirai, M., et al. 2013. Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor. Am J Physiol Heart Circ Physiol 305:H155-162.
28. Sanli, C., Oguz, D., Olgunturk, R., Tunaoglu, F.S., Kula, S., Pasaoglu, H., Gulbahar, O., and Cevik, A. 2012. Elevated homocysteine and asymmetric dimethyl arginine levels in pulmonary hypertension associated with congenital heart disease. Pediatr Cardiol 33:1323-1331.
29. Arroliga, A.C., Sandur, S., Jacobsen, D.W., Tewari, S., Mustafa, M., Mascha, E.J., and Robinson, K. 2003. Association between hyperhomocysteinemia and primary pulmonary hypertension. Respir Med 97:825-829.
30. Yuditskaya, S., Tumblin, A., Hoehn, G.T., Wang, G., Drake, S.K., Xu, X., Ying, S., Chi, A.H., Remaley, A.T., Shen, R.F., et al. 2009. Proteomic identification of altered apolipoprotein patterns in pulmonary hypertension and vasculopathy of sickle cell disease. Blood 113:1122-1128.
31. Yano, T., Sogawa, K., Umemura, H., Sakao, S., Kasahara, Y., Tanabe, N., Kodera, Y., Takiguchi, Y., Tatsumi, K., and Nomura, F. 2011. Serum level of fibrinogen Aalpha chain fragment increases in chronic thromboembolic pulmonary hypertension. Circ J 75:2675-2682.
32. Quarck, R., Nawrot, T., Meyns, B., and Delcroix, M. 2009. C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol 53:1211-1218.