Evidence for Angiotensin-converting Enzyme 2 as a Therapeutic Target for the Prevention of Pulmonary Hypertension

被引:223
作者
Ferreira, Anderson J. [1 ]
Shenoy, Vinayak [2 ]
Yamazato, Yoriko [1 ]
Sriramula, Srinivas [3 ]
Francis, Joseph [3 ]
Yuan, Lihui [1 ]
Castellano, Ronald K. [4 ]
Ostrov, David A. [5 ]
Oh, Suk Paul [1 ]
Katovich, Michael J. [2 ]
Raizada, Mohan K. [1 ]
机构
[1] Univ Florida, Coll Med, Dept Physiol & Funct Genom, Gainesville, FL 32610 USA
[2] Univ Florida, Coll Pharm, Dept Pharmacodynam, Gainesville, FL 32610 USA
[3] Louisiana State Univ, Sch Vet Med, Baton Rouge, LA 70803 USA
[4] Univ Florida, Coll Liberal Arts & Sci, Dept Chem, Gainesville, FL 32610 USA
[5] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA
关键词
renin angiotensin system; angiotensin-converting enzyme 2; pulmonary heart disease; MONOCYTE CHEMOATTRACTANT PROTEIN-1; ARTERIAL-HYPERTENSION; GENE-THERAPY; ACE2; MECHANISMS; HYPOXIA; LUNG; ANGIOTENSIN-CONVERTING-ENZYME-2; PATHOGENESIS; INFLAMMATION;
D O I
10.1164/rccm.200811-1678OC
中图分类号
R4 [临床医学];
学科分类号
100218 [急诊医学];
摘要
Rationale It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH. Objectives: We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxyl-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. Methods: The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. Measurements and Main Results: A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. Conclusions: These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.
引用
收藏
页码:1048 / 1054
页数:7
相关论文
共 33 条
[1]
Circulating endothelial microparticle levels predict hemodynamic severity of pulmonary hypertension [J].
Amabile, Nicolas ;
Heiss, Christian ;
Real, Wendy May ;
Minasi, Petros ;
McGlothlin, Dana ;
Rame, Eduardo J. ;
Grossman, William ;
De Marco, Teresa ;
Yeghiazarians, Yerem .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2008, 177 (11) :1268-1275
[2]
BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia [J].
Beppu, H ;
Ichinose, F ;
Kawai, N ;
Jones, RC ;
Yu, PB ;
Zapol, WM ;
Miyazono, K ;
Li, E ;
Bloch, KD .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2004, 287 (06) :L1241-L1247
[3]
Pathogenic mechanisms of pulmonary arterial hypertension [J].
Chan, Stephen Y. ;
Loscalzo, Joseph .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2008, 44 (01) :14-30
[4]
Pulmonary arterial hypertension [J].
Chin, Kelly M. ;
Rubin, Lewis J. .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2008, 51 (16) :1527-1538
[5]
ELWING J, 2008, J CHRON OBSTRUCT PUL, V3, P55
[6]
Ferreira AJ, 2008, J HYPERTENS, V26, pS20
[7]
Ferreira AJ, 2008, HYPERTENSION, V52, pE62
[8]
Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis [J].
Hamming, I ;
Timens, W ;
Bulthuis, MLC ;
Lely, AT ;
Navis, GJ ;
van Goor, H .
JOURNAL OF PATHOLOGY, 2004, 203 (02) :631-637
[9]
The emerging role of ACE2 in physiology and disease [J].
Hamming, I. ;
Cooper, M. E. ;
Haagmans, B. L. ;
Hooper, N. M. ;
Korstanje, R. ;
Osterhaus, A. D. M. E. ;
Timens, W. ;
Turner, A. J. ;
Navis, G. ;
van Goor, H. .
JOURNAL OF PATHOLOGY, 2007, 212 (01) :1-11
[10]
FACTORS DETERMINING DEGREE OF INFLATION IN INTRATRACHEALLY FIXED RAT LUNGS [J].
HAYATDAVOUDI, G ;
CRAPO, JD ;
MILLER, FJ ;
ONEIL, JJ .
JOURNAL OF APPLIED PHYSIOLOGY, 1980, 48 (02) :389-393