title: Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression.
abstract: 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.
authors.affiliation: 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
authors.forename: Jiu-Chang
authors.initials: JC
authors.lastname: Zhong
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Ye
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Jin
authors.forename: Xi
authors.initials: X
authors.lastname: Yu
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Yu
authors.forename: Ding-Liang
authors.initials: DL
authors.lastname: Zhu
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
authors.forename: Dong-Yang
authors.initials: DY
authors.lastname: Huang
authors.forename: Manfred
authors.initials: M
authors.lastname: Shuster
authors.forename: Hans
authors.initials: H
authors.lastname: Loibner
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Guo
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Bing-Xiu
authors.initials: BX
authors.lastname: Xiao
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Gong
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: 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
chemical_list: 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