Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects

被引:190
作者
Iwata, M
Cowling, RT
Gurantz, D
Moore, C
Zhang, S
Yuan, JXJ
Greenberg, BH
机构
[1] Univ Calif San Diego, Med Ctr, Dept Med Cardiol, Div Cardiol, San Diego, CA 92103 USA
[2] Univ Calif San Diego, Dept Med, Div Pulm & Crit Care, San Diego, CA 92103 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2005年 / 289卷 / 06期
关键词
angiotensin receptors; cardiac remodeling; renin-angiotensin system;
D O I
10.1152/ajpheart.00317.2005
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
ANG-(1-7) improves the function of the remodeling heart. Although this peptide is generated directly within the myocardium, the effects of ANG-(1-7) on cardiac fibroblasts that play a critical role in cardiac remodeling are largely unknown. We tested the hypothesis that specific binding of ANG-(1-7) to cardiac fibroblasts regulates cellular functions that are involved in cardiac remodeling. I-125-labeled ANG-(1-7) binding assays identified specific binding sites of ANG-(1-7) on adult rat cardiac fibroblasts (ARCFs) with an affinity of 11.3 nM and a density of 131 fmol/mg protein. At nanomolar concentrations, ANG-(1-7) interacted with specific sites that were distinct from ANG II type 1 and type 2 receptors without increasing cytosolic Ca2+ concentration. At these concentrations, ANG-(1-7) had inhibitory effects on collagen synthesis as assessed by [H-3] proline incorporation and decreased mRNA expression of growth factors in ARCFs. These effects of ANG-(1-7) contrasted with effects of ANG II. Pretreatment of ARCFs with ANG-(1-7) inhibited ANG II-induced increases in collagen synthesis and in mRNA expression of growth factors, including endothelin-1 and leukemia inhibitory factor. ANG-(1-7) pretreatment also inhibited the stimulatory effects of conditioned medium from ANG II-treated ARCFs on [H-3] leucine incorporation and atrial natriuretic factor mRNA expression, markers of hypertrophy, in cardiomyocytes. Thus ANG-(1-7) interacted with specific receptors on ARCFs to exert potential antifibrotic and antitrophic effects that could reverse ANG II effects. These results suggest that ANG-(1-7) may play an important role in the heart in regulating cardiac remodeling.
引用
收藏
页码:H2356 / H2363
页数:8
相关论文
共 30 条
[1]   Cardiac angiotensin-(1-7) in ischemic cardiomyopathy [J].
Averill, DB ;
Ishiyama, Y ;
Chappell, MC ;
Ferrario, CM .
CIRCULATION, 2003, 108 (17) :2141-2146
[2]   Angiotensin-(1-7) downregulates the angiotensin II type 1 receptor in vascular smooth muscle cells [J].
Clark, MA ;
Diz, DI ;
Tallant, EA .
HYPERTENSION, 2001, 37 (04) :1141-1146
[3]   Transcription factor NF-κB is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factor-α or interleukin-1β [J].
Cowling, RT ;
Gurantz, D ;
Peng, JF ;
Dillmann, WH ;
Greenberg, BH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (08) :5719-5724
[4]   CHARACTERIZATION OF ANGIOTENSIN-II RECEPTORS IN CULTURED ADULT-RAT CARDIAC FIBROBLASTS - COUPLING TO SIGNALING SYSTEMS AND GENE-EXPRESSION [J].
CRABOS, M ;
ROTH, M ;
HAHN, AWA ;
ERNE, P .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (06) :2372-2378
[5]   Angiotensin-converting enzyme 2 is an essential regulator of heart function [J].
Crackower, MA ;
Sarao, R ;
Oudit, GY ;
Yagil, C ;
Kozieradzki, I ;
Scanga, SE ;
Oliveira-dos-Santos, AJ ;
da Costa, J ;
Zhang, LY ;
Pei, Y ;
Scholey, J ;
Ferrario, CM ;
Manoukian, AS ;
Chappell, MC ;
Backx, PH ;
Yagil, Y ;
Penninger, JM .
NATURE, 2002, 417 (6891) :822-828
[6]   Compartmentalization of angiotensin II generation in the dog heart - Evidence for independent mechanisms in intravascular and interstitial spaces [J].
DellItalia, LJ ;
Meng, QC ;
Balcells, E ;
Wei, CC ;
Palmer, R ;
Hageman, GR ;
Durand, J ;
Hankes, GH ;
Oparil, S .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (02) :253-258
[7]   The cardiac renin-angiotensin system - Conceptual, or a regulator of cardiac function? [J].
Dostal, DE ;
Baker, KM .
CIRCULATION RESEARCH, 1999, 85 (07) :643-650
[8]  
DOUNOHUE M, 2000, CIRC RES, V87, pE1
[9]   Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-β1 and endothelin-1 from fibroblasts [J].
Gray, MO ;
Long, CS ;
Kalinyak, JE ;
Li, HT ;
Karliner, JS .
CARDIOVASCULAR RESEARCH, 1998, 40 (02) :352-363
[10]   Tumor necrosis factor-α upregulates angiotensin II type 1 receptors on cardiac fibroblasts [J].
Gurantz, D ;
Cowling, RT ;
Villarreal, FJ ;
Greenberg, BH .
CIRCULATION RESEARCH, 1999, 85 (03) :272-279