Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression.
Profilin-1 has recently been linked to vascular hypertrophy and remodeling. Here, we assessed the hypothesis that angiotensin (Ang) II type I receptor antagonist telmisartan improves vascular hypertrophy by modulation of expression of profilin-1 and angiotensin-converting enzyme 2 (ACE2). Ten-week-old male spontaneously hypertensive rats (SHR) were received oral administration of telmisartan (5 or 10mg/kg; daily) or saline for 10 weeks. Compared with Wistar-Kyoto (WKY) rats, there were marked increases in systolic blood pressure and profilin-1 expression and reduced ACE2 and peroxisome proliferator activated receptor-γ (PPARγ) levels in aorta of SHR, associated with elevated extracellular-signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) phosphorylation signaling and aortic hypertrophy characterized with increased media thickness, which were strikingly reversed by telmisartan. In cultured human umbilical artery smooth muscle cells (HUASMCs), Ang II induced a dose-dependent increase in profilin-1 expression, along with decreased ACE2 protein expression and elevated ERK1/2 and JNK phosphorylation. In addition, blockade of ERK1/2 or JNK by either specific inhibitor was able to abolish Ang II-induced ACE2 downregulation and profilin-1 upregulation in HUASMCs. Importantly, treatment with telmisartan (1 or 10 μM) or recombinant human ACE2 (2mg/ml) largely ameliorated Ang II-induced profilin-1 expression and ERK1/2 and JNK phosphorylation and augmented PPARγ expression in the cultured HUASMCs. In conclusion, telmisartan treatment attenuates vascular hypertrophy in SHR by the modulation of ACE2 and profilin-1 expression with a marked reversal of ERK1/2 and JNK phosphorylation signaling pathways.
Zhong
Jiu-Chang
JC
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Vascular Biology, Shanghai Institute of Hypertension, Shanghai 200025, China. jiuchangzhong@yahoo.com.cn
Ye
Jia-Ying
JY
Jin
Hai-Yan
HY
Yu
Xi
X
Yu
Hui-Min
HM
Zhu
Ding-Liang
DL
Gao
Ping-Jin
PJ
Huang
Dong-Yang
DY
Shuster
Manfred
M
Loibner
Hans
H
Guo
Jun-Min
JM
Yu
Xi-Yong
XY
Xiao
Bing-Xiu
BX
Gong
Zhao-Hui
ZH
Penninger
Josef M
JM
Oudit
Gavin Y
GY
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D002478:Cells, Cultured; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D047495:PPAR gamma / Q000096:biosynthesis; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000378:metabolism; D051304:Profilins / Q000096:biosynthesis* / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan
D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D051304:Profilins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D000077333:Telmisartan