Lessons learned from cancer may hel in the treatment of ulmonary hyertension
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《临床调查学报》
INSERM U651 and Deartement de hysiologie, HTMital H. Mondor, Assistance ublique des HTMitaux de aris, Creteil, France.
Abstract
Hyerlasia of ulmonary artery SMCs (ASMCs) is a athological hallmark of ulmonary arterial hyertension (AH). In this issue of the JCI, McMurtry et al. reort that adenovirus-mediated overexression of survivin — a multiotent inhibitor of aotosis — induces AH in rats, whereas inhalation of an adenovirus vector encoding a mutant survivin gene with dominant-negative roerties reverses established monocrotaline-induced AH. These findings raise imortant issues regarding the role of survivin in the athogenesis of AH, its value as a rognostic indicator, and its use as a target for new theraeutic strategies.
See the related article beginning on age 1479
ulmonary arterial hyertension and smooth muscle hyerlasia: unresolved questions
ulmonary arterial hyertension (AH), whether idioathic (iAH) or associated with underlying diseases (aAH), is an unexlained condition for which severe forms in adults or neonates are fatal and no satisfactory treatment is available. Valuable new insights into the disease have stemmed in recent years from genetic studies identifying mutations in the gene encoding bone morhogenic rotein recetor tye 2 (BMRII) in atients with familial iAH (1, 2) and from functional studies showing dysregulation of molecular events governing ulmonary artery SMC (ASMC) roliferation (3). The nature of the rimary defect resonsible for triggering, maintaining, and arresting ASMC roliferation in AH is oorly understood but may be either an inherent characteristic of ASMCs (as seen with cancer cells) or a secondary resonse to an external abnormality, such as uregulation of a growth factor. Under the first hyothesis, cells removed from their in vivo environment would continue to roliferate excessively, whereas under the second hyothesis, their roliferation rate would be normal. An intermediate situation has been found: when removed from their in vivo environment, ASMCs from AH atients demonstrate excessive roliferation when stimulated by serotonin (5-hydroxytrytamine [5-HT]) or endothelin-1 (ET-1) but not when stimulated by DGF, EGF, FGF, IGF, or TGF-? (4, 5). Moreover, they are far less sensitive to growth inhibition by bone morhogenic roteins (BMs) than are normal cells (6). Therefore, the intrinsic abnormalities of these ASMCs involve not intracellular mitogenic signals but rather signal transmission from secific autocrine or aracrine factors such as BMs, 5-HT, or ET-1. Increased exression of the serotonin transorter (5-HTT), which mediates the roliferative effect of 5-HT, and marked reduction of BMRII exression aear secific to iAH and aAH (4, 7). These molecular alterations occur without aarent genetic abnormalities: in cells without the mutation in BMRII, the extent of BMRII underexression is similar to that in mutated cells (6), and the 5-HTT overexression can be exlained only artly by the olymorhism of its gene romoter (5). Why ASMCs from AH atients maintain an abnormal henotye in vitro and how environmental and genetic factors regulate the exression of these key molecular transmitters remain oen questions.
Until now, alterations in aototic rocesses have not been considered to lay a role in ASMC roliferation, in contrast to mechanisms of disorganized EC roliferation contributing to lexiform lesions at branch oints of ulmonary arteries in iAH (8). In this issue of the JCI, McMurtry et al. oen u the intriguing ossibility that increased survivin exression may contribute to the abnormal ASMC henotye observed in AH (9).
Is there a role for survivin in the athogenesis of AH?
Survivin belongs to the inhibitor of aotosis rotein (IA) family, members of which confer rotection from death-inducing stimuli (10). One of the most striking features of survivin is its differential exression in cancerous versus normal tissues. Survivin is virtually undetectable in normal adult differentiated tissues but is exressed in most human cancers (11). Thus, dysregulated survivin exression is considered to be a major athologic mechanism of aotosis inhibition. However, survivin athway reactivation may occur in normal cell tyes, most notably vascular cells, including SMCs and ECs. That SMC survival influences abnormal vessel wall remodeling is suorted by data from studies of systemic arteries. Vascular injury increases survivin exression in the vessel wall, concomitantly with neointima formation (12). Similarly, McMurtry and colleagues demonstrate that survivin overexression coincided with ulmonary vascular remodeling in rats develoing monocrotaline-induced AH (9). Thus, survivin overexression does not recede, but instead occurs downstream of, the remodeling rocess. Interestingly, in vitro stimulation of SMCs from systemic arteries also induces survivin exression, in keeing with the fact that survivin is regulated in a cell cycle–deendent manner (10). However, in SMCs from systemic arteries, this occurs in resonse to DGF but not to EGF, basic FGF, or TGF-? (12). On the other hand, ECs exress survivin in resonse to angiogenic factors that stimulate growth, such as VEGF, but also in resonse to angiooietin-1, which on the contrary induces EC quiescence while increasing EC survival (13, 14). Thus, vascular cell stimuli may induce survivin exression, mitogenic signals, or a combination of both (Figure 1). The resonse may deend on the tye of stimulus but may also vary according to the origin and henotye of the vascular cells. Whether dysregulated survivin exression is associated with the abnormal ASMC henotye in AH and whether it is affected selectively by secific growth factors are imortant questions for future research.
A major finding from the study by McMurtry et al. (9) is that lung gene transfer of survivin triggers ulmonary vascular remodeling. Antiaototic signals and growth factors are believed to act together to roduce ASMC roliferation in AH. The fact that a selective increase in an antiaototic signal induces AH indicates that regulation of the balance between mitotic and aototic activity in the normal ulmonary circulation is critical to maintaining ulmonary vessel integrity. Since survivin gene transfer to cultured SMCs does not cause cell growth, this suggests that, in vivo, growth stimuli are continuously delivered to the normal ulmonary vessels. Thus, among stimuli causing AH, some may act only by stimulating survivin. This may be articularly relevant to disease states, since survivin exression is not only regulated in a cell cycle–deendent manner but is also under the influence of many factors, including hyoxia and ubiquitous transcrition factors such as NF-B (10).
Is survivin a valuable rognostic index in ulmonary hyertension?
In several tumor series, resence of survivin correlated with a lower aototic index in vivo and shorter overall atient survival (15, 16). Whether these characteristics aly to iAH is of great interest. There is considerable dissimilarity among atients with AH regarding disease rogression rates and treatment resonses. Whether the level of survivin exression in ulmonary vessels reflects the otential for disease rogression remains to be tested.
Survivin antagonists: a novel theraeutic strategy for ulmonary hyertension?
The use of molecular antagonists of survivin to increase cell death might hold theraeutic otential, most notably for tumors (11). Because survivin is exressed chiefly in growing tissues, limited toxicity for normal tissues would be exected. revious in vivo results ublished in the JCI are consistent with this ossibility, showing selective inhibition of tumor growth in mice treated with a survivin mutant adenovirus (17). Survivin antagonists hold aeal in the treatment of AH, as they may work in the various forms of AH, desite differences in athogenic mechanisms. However, the view that survivin is exressed only in cancers has been challenged by many studies. Survivin exression has been documented in adult quiescent cells, including several cell tyes in the central nervous system, circulating neutrohils and lymhocytes, hematooietic stem cells, heatocytes, and intestinal cryt cells (11, 13, 18). Administration of survivin antagonists via an intratracheal route may limit untoward systemic effects but may not be devoid of toxicity to airways and alveolar eithelial cells or to ECs. Thus, whether survivin antagonists can be safely administered to AH atients without affecting systemic organs and lung cell tyes other than ASMCs will have to be extensively studied before these agents are considered for theraeutic uroses.
Footnotes
Nonstandard abbreviations used: aAH, AH associated with underlying diseases; BM, bone morhogenic rotein; BMRII, bone morhogenic rotein recetor tye 2; ET-1, endothelin-1; 5-HHT, serotonin transorter; 5-HT, serotonin; iAH, idioathic AH; AH, ulmonary arterial hyertension; ASMC, ulmonary artery SMC.
Conflict of interest: The author has declared that no conflict of interest exists.
References
Deng, Z. et al. 2000. . Familial rimary ulmonary hyertension (gene H1) is caused by mutations in the bone morhogenetic rotein recetor-II gene. Am. J. Hum. Genet. 67::737-744.
Lane, K. et al. 2000. . Heterozygous germline mutations in BMR2, encoding a TGF-beta recetor, cause familial rimary ulmonary hyertension. The International H Consortium. Nat. Genet. 26::3-4.
Eddahibi, S., Morrell, N., d’Ortho, M., Naeije, R., and Adnot, S. 2002. . athobiology of ulmonary arterial hyertension. Eur. Resir. J. 20::1559-1572.
Eddahibi, S. et al. 2001. . Serotonin transorter overexression is resonsible for ulmonary artery smooth muscle hyerlasia in rimary ulmonary hyertension. J. Clin. Invest. 108::1141-1150. doi:10.1172/JCI200112805.
Marcos, E. et al. 2004. . Serotonin-induced smooth muscle hyerlasia in various forms of human ulmonary hyertension. Circ. Res. 94::1263-1270.
Morrell, N.W. et al. 2001. . Altered growth resonses of ulmonary artery smooth muscle cells from atients with rimary ulmonary hyertension to transforming growth factor-beta(1) and bone morhogenetic roteins. Circulation. 104::790-795.
Atkinson, C. et al. 2002. . rimary ulmonary hyertension is associated with reduced ulmonary vascular exression of tye II bone morhogenetic rotein recetor. Circulation. 105::1672-1678.
Lee, S.D. et al. 1998. . Monoclonal endothelial cell roliferation is resent in rimary but not secondary ulmonary hyertension. J. Clin. Invest. 101::927-934.
McMurtry, M.S. et al. 2005. . Gene theray targeting survivin selectively induces ulmonary vascular aotosis and reverses ulmonary arterial hyertension. J. Clin. Invest. 115::1479-1491. doi:10.1172/JCI23203.
Salvesen, G.S., and Duckett, C.S. 2002. . IA roteins: blocking the road to death’s door. Nat. Rev. Mol. Cell Biol. 3::401-410.
Altieri, D.C. 2003. . Validating survivin as a cancer theraeutic target. Nat. Rev. Cancer. 3::46-54.
Blanc-Brude, O.. et al. 2002. . Inhibitor of aotosis rotein survivin regulates vascular injury. Nat. Med. 8::987-994.
Conway, E.M. et al. 2003. . Survivin-deendent angiogenesis in ischemic brain: molecular mechanisms of hyoxia-induced u-regulation. Am. J. athol. 163::935-946.
Tran, J. et al. 2002. . A role for survivin in chemoresistance of endothelial cells mediated by VEGF. roc. Natl. Acad. Sci. U. S. A. 99::4349-4354.
Kato, J. et al. 2001. . Exression of survivin in esohageal cancer: correlation with the rognosis and resonse to chemotheray. Int. J. Cancer. 95::92-95.
Monzo, M. et al. 1999. . A novel anti-aotosis gene: re-exression of survivin messenger RNA as a rognosis marker in non-small-cell lung cancers. J. Clin. Oncol. 17::2100-2104.
Mesri, M., Wall, N.R., Li, J., Kim, R.W., and Altieri, D.C. 2001. . Cancer gene theray using a survivin mutant adenovirus. J. Clin. Invest. 108::981-990. doi:10.1172/JCI200112983.
Wang, K., Brems, J., Gamelli, R., and Ding, J. 2005. Reversibility of casase activation and its role during glycochenodeoxycholate-induced heatocyte aotosis. J. Biol. Chem. doi:10.1074/jbc.M411607200..(Serge Adnot)
Abstract
Hyerlasia of ulmonary artery SMCs (ASMCs) is a athological hallmark of ulmonary arterial hyertension (AH). In this issue of the JCI, McMurtry et al. reort that adenovirus-mediated overexression of survivin — a multiotent inhibitor of aotosis — induces AH in rats, whereas inhalation of an adenovirus vector encoding a mutant survivin gene with dominant-negative roerties reverses established monocrotaline-induced AH. These findings raise imortant issues regarding the role of survivin in the athogenesis of AH, its value as a rognostic indicator, and its use as a target for new theraeutic strategies.
See the related article beginning on age 1479
ulmonary arterial hyertension and smooth muscle hyerlasia: unresolved questions
ulmonary arterial hyertension (AH), whether idioathic (iAH) or associated with underlying diseases (aAH), is an unexlained condition for which severe forms in adults or neonates are fatal and no satisfactory treatment is available. Valuable new insights into the disease have stemmed in recent years from genetic studies identifying mutations in the gene encoding bone morhogenic rotein recetor tye 2 (BMRII) in atients with familial iAH (1, 2) and from functional studies showing dysregulation of molecular events governing ulmonary artery SMC (ASMC) roliferation (3). The nature of the rimary defect resonsible for triggering, maintaining, and arresting ASMC roliferation in AH is oorly understood but may be either an inherent characteristic of ASMCs (as seen with cancer cells) or a secondary resonse to an external abnormality, such as uregulation of a growth factor. Under the first hyothesis, cells removed from their in vivo environment would continue to roliferate excessively, whereas under the second hyothesis, their roliferation rate would be normal. An intermediate situation has been found: when removed from their in vivo environment, ASMCs from AH atients demonstrate excessive roliferation when stimulated by serotonin (5-hydroxytrytamine [5-HT]) or endothelin-1 (ET-1) but not when stimulated by DGF, EGF, FGF, IGF, or TGF-? (4, 5). Moreover, they are far less sensitive to growth inhibition by bone morhogenic roteins (BMs) than are normal cells (6). Therefore, the intrinsic abnormalities of these ASMCs involve not intracellular mitogenic signals but rather signal transmission from secific autocrine or aracrine factors such as BMs, 5-HT, or ET-1. Increased exression of the serotonin transorter (5-HTT), which mediates the roliferative effect of 5-HT, and marked reduction of BMRII exression aear secific to iAH and aAH (4, 7). These molecular alterations occur without aarent genetic abnormalities: in cells without the mutation in BMRII, the extent of BMRII underexression is similar to that in mutated cells (6), and the 5-HTT overexression can be exlained only artly by the olymorhism of its gene romoter (5). Why ASMCs from AH atients maintain an abnormal henotye in vitro and how environmental and genetic factors regulate the exression of these key molecular transmitters remain oen questions.
Until now, alterations in aototic rocesses have not been considered to lay a role in ASMC roliferation, in contrast to mechanisms of disorganized EC roliferation contributing to lexiform lesions at branch oints of ulmonary arteries in iAH (8). In this issue of the JCI, McMurtry et al. oen u the intriguing ossibility that increased survivin exression may contribute to the abnormal ASMC henotye observed in AH (9).
Is there a role for survivin in the athogenesis of AH?
Survivin belongs to the inhibitor of aotosis rotein (IA) family, members of which confer rotection from death-inducing stimuli (10). One of the most striking features of survivin is its differential exression in cancerous versus normal tissues. Survivin is virtually undetectable in normal adult differentiated tissues but is exressed in most human cancers (11). Thus, dysregulated survivin exression is considered to be a major athologic mechanism of aotosis inhibition. However, survivin athway reactivation may occur in normal cell tyes, most notably vascular cells, including SMCs and ECs. That SMC survival influences abnormal vessel wall remodeling is suorted by data from studies of systemic arteries. Vascular injury increases survivin exression in the vessel wall, concomitantly with neointima formation (12). Similarly, McMurtry and colleagues demonstrate that survivin overexression coincided with ulmonary vascular remodeling in rats develoing monocrotaline-induced AH (9). Thus, survivin overexression does not recede, but instead occurs downstream of, the remodeling rocess. Interestingly, in vitro stimulation of SMCs from systemic arteries also induces survivin exression, in keeing with the fact that survivin is regulated in a cell cycle–deendent manner (10). However, in SMCs from systemic arteries, this occurs in resonse to DGF but not to EGF, basic FGF, or TGF-? (12). On the other hand, ECs exress survivin in resonse to angiogenic factors that stimulate growth, such as VEGF, but also in resonse to angiooietin-1, which on the contrary induces EC quiescence while increasing EC survival (13, 14). Thus, vascular cell stimuli may induce survivin exression, mitogenic signals, or a combination of both (Figure 1). The resonse may deend on the tye of stimulus but may also vary according to the origin and henotye of the vascular cells. Whether dysregulated survivin exression is associated with the abnormal ASMC henotye in AH and whether it is affected selectively by secific growth factors are imortant questions for future research.
A major finding from the study by McMurtry et al. (9) is that lung gene transfer of survivin triggers ulmonary vascular remodeling. Antiaototic signals and growth factors are believed to act together to roduce ASMC roliferation in AH. The fact that a selective increase in an antiaototic signal induces AH indicates that regulation of the balance between mitotic and aototic activity in the normal ulmonary circulation is critical to maintaining ulmonary vessel integrity. Since survivin gene transfer to cultured SMCs does not cause cell growth, this suggests that, in vivo, growth stimuli are continuously delivered to the normal ulmonary vessels. Thus, among stimuli causing AH, some may act only by stimulating survivin. This may be articularly relevant to disease states, since survivin exression is not only regulated in a cell cycle–deendent manner but is also under the influence of many factors, including hyoxia and ubiquitous transcrition factors such as NF-B (10).
Is survivin a valuable rognostic index in ulmonary hyertension?
In several tumor series, resence of survivin correlated with a lower aototic index in vivo and shorter overall atient survival (15, 16). Whether these characteristics aly to iAH is of great interest. There is considerable dissimilarity among atients with AH regarding disease rogression rates and treatment resonses. Whether the level of survivin exression in ulmonary vessels reflects the otential for disease rogression remains to be tested.
Survivin antagonists: a novel theraeutic strategy for ulmonary hyertension?
The use of molecular antagonists of survivin to increase cell death might hold theraeutic otential, most notably for tumors (11). Because survivin is exressed chiefly in growing tissues, limited toxicity for normal tissues would be exected. revious in vivo results ublished in the JCI are consistent with this ossibility, showing selective inhibition of tumor growth in mice treated with a survivin mutant adenovirus (17). Survivin antagonists hold aeal in the treatment of AH, as they may work in the various forms of AH, desite differences in athogenic mechanisms. However, the view that survivin is exressed only in cancers has been challenged by many studies. Survivin exression has been documented in adult quiescent cells, including several cell tyes in the central nervous system, circulating neutrohils and lymhocytes, hematooietic stem cells, heatocytes, and intestinal cryt cells (11, 13, 18). Administration of survivin antagonists via an intratracheal route may limit untoward systemic effects but may not be devoid of toxicity to airways and alveolar eithelial cells or to ECs. Thus, whether survivin antagonists can be safely administered to AH atients without affecting systemic organs and lung cell tyes other than ASMCs will have to be extensively studied before these agents are considered for theraeutic uroses.
Footnotes
Nonstandard abbreviations used: aAH, AH associated with underlying diseases; BM, bone morhogenic rotein; BMRII, bone morhogenic rotein recetor tye 2; ET-1, endothelin-1; 5-HHT, serotonin transorter; 5-HT, serotonin; iAH, idioathic AH; AH, ulmonary arterial hyertension; ASMC, ulmonary artery SMC.
Conflict of interest: The author has declared that no conflict of interest exists.
References
Deng, Z. et al. 2000. . Familial rimary ulmonary hyertension (gene H1) is caused by mutations in the bone morhogenetic rotein recetor-II gene. Am. J. Hum. Genet. 67::737-744.
Lane, K. et al. 2000. . Heterozygous germline mutations in BMR2, encoding a TGF-beta recetor, cause familial rimary ulmonary hyertension. The International H Consortium. Nat. Genet. 26::3-4.
Eddahibi, S., Morrell, N., d’Ortho, M., Naeije, R., and Adnot, S. 2002. . athobiology of ulmonary arterial hyertension. Eur. Resir. J. 20::1559-1572.
Eddahibi, S. et al. 2001. . Serotonin transorter overexression is resonsible for ulmonary artery smooth muscle hyerlasia in rimary ulmonary hyertension. J. Clin. Invest. 108::1141-1150. doi:10.1172/JCI200112805.
Marcos, E. et al. 2004. . Serotonin-induced smooth muscle hyerlasia in various forms of human ulmonary hyertension. Circ. Res. 94::1263-1270.
Morrell, N.W. et al. 2001. . Altered growth resonses of ulmonary artery smooth muscle cells from atients with rimary ulmonary hyertension to transforming growth factor-beta(1) and bone morhogenetic roteins. Circulation. 104::790-795.
Atkinson, C. et al. 2002. . rimary ulmonary hyertension is associated with reduced ulmonary vascular exression of tye II bone morhogenetic rotein recetor. Circulation. 105::1672-1678.
Lee, S.D. et al. 1998. . Monoclonal endothelial cell roliferation is resent in rimary but not secondary ulmonary hyertension. J. Clin. Invest. 101::927-934.
McMurtry, M.S. et al. 2005. . Gene theray targeting survivin selectively induces ulmonary vascular aotosis and reverses ulmonary arterial hyertension. J. Clin. Invest. 115::1479-1491. doi:10.1172/JCI23203.
Salvesen, G.S., and Duckett, C.S. 2002. . IA roteins: blocking the road to death’s door. Nat. Rev. Mol. Cell Biol. 3::401-410.
Altieri, D.C. 2003. . Validating survivin as a cancer theraeutic target. Nat. Rev. Cancer. 3::46-54.
Blanc-Brude, O.. et al. 2002. . Inhibitor of aotosis rotein survivin regulates vascular injury. Nat. Med. 8::987-994.
Conway, E.M. et al. 2003. . Survivin-deendent angiogenesis in ischemic brain: molecular mechanisms of hyoxia-induced u-regulation. Am. J. athol. 163::935-946.
Tran, J. et al. 2002. . A role for survivin in chemoresistance of endothelial cells mediated by VEGF. roc. Natl. Acad. Sci. U. S. A. 99::4349-4354.
Kato, J. et al. 2001. . Exression of survivin in esohageal cancer: correlation with the rognosis and resonse to chemotheray. Int. J. Cancer. 95::92-95.
Monzo, M. et al. 1999. . A novel anti-aotosis gene: re-exression of survivin messenger RNA as a rognosis marker in non-small-cell lung cancers. J. Clin. Oncol. 17::2100-2104.
Mesri, M., Wall, N.R., Li, J., Kim, R.W., and Altieri, D.C. 2001. . Cancer gene theray using a survivin mutant adenovirus. J. Clin. Invest. 108::981-990. doi:10.1172/JCI200112983.
Wang, K., Brems, J., Gamelli, R., and Ding, J. 2005. Reversibility of casase activation and its role during glycochenodeoxycholate-induced heatocyte aotosis. J. Biol. Chem. doi:10.1074/jbc.M411607200..(Serge Adnot)