Intra-coronary administration of soluble receptor for advanced glycation end-products attenuates cardiac remodeling with decreased myocardial transforming growth factor-beta1 expression and fibrosis in minipigs with ischemia-reperfusion injury.
BACKGROUND
The cardioprotective effects of soluble receptor for advanced glycation end-products (sRAGE) have not been evaluated in large animals and the underlying mechanisms are not fully understood. This study aimed to evaluate the effects of intra-coronary administration of sRAGE on left ventricular function and myocardial remodeling in a porcine model of ischemia-reperfusion (I/R) injury.


METHODS
Ten male minipigs with I/R injury were randomly allocated to receive intra-coronary administration of sRAGE (sRAGE group, n = 5) or saline (control group, n = 5). Echocardiography was performed before and 2 months after infarction. Myocardial expression of transforming growth factor (TGF)-beta1 was determined by immunohistochemistry and fibrosis was evaluated by Sirius red staining.


RESULTS
As compared with the baseline values in the control animals, left ventricular end-diastolic volume (from (19.5 +/- 5.1) to (32.3 +/- 5.6) ml, P < 0.05) and end-systolic volume (from (8.3 +/- 3.2) to (15.2 +/- 4.1) ml, P< 0.05) were significantly increased, whereas ejection fraction was decreased (from (61.6 +/- 13.3)% to (50.2 +/- 11.9)%, P < 0.05). No obvious change in these parameters was observed in the sRAGE group. Myocardial expression of TGF-beta1 was significantly elevated in the infarct and non-infarct regions in the control group, as compared with sRAGE group (both P< 0.01). Fibrotic lesions were consistently more prominent in the infarct region of the myocardium in the control animals (P < 0.05).


CONCLUSIONS
Intra-coronary sRAGE administration attenuates RAGE-mediated myocardial fibrosis and I/R injury through a TGF-beta1-dependent mechanism, suggesting a clinical potential in treating RAGE/ligand-associated cardiovascular diseases.
Lu
Lin
L
Department of Cardiology, Ruijin Hospital, Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Zhang
Qi
Q
Xu
Yan
Y
Zhu
Zheng-bin
ZB
Geng
Liang
L
Wang
Ling-jie
LJ
Jin
Cao
C
Chen
Qiu-jing
QJ
Schmidt
Ann Marie
AM
Shen
Wei-feng
WF
D000818:Animals; D004452:Echocardiography; D005355:Fibrosis; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage*; D015427:Reperfusion Injury; D013552:Swine; D013556:Swine, Miniature; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D020257:Ventricular Remodeling
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1