Angiotensin II AT1 receptor alters ACE2 activity, eNOS expression and CD44-hyaluronan interaction in rats with hypertension and myocardial fibrosis
Authors: Ning-Ping Wang
Robert J McKallip
Xue-Fen Pang
Li-Hui Zhang
Zhi-Qing Zhao
Ronald E Garner
Feng Bai
Journal: Life Sciences (2016)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Angiotensin II AT1 receptor; Angiotensin converting enzyme 2; CD44; Collagen; Hyaluronan
Affiliations: Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China., Department of Cardiology, Shanxi Academy of Medical Sciences and Shanxi Dayi Hospital, Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China., Basic Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA., Division of Basic Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA., Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China; Basic Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA. Electronic address: .

Abstract:  Aim: This study tested the hypothesis that angiotensin II (Ang II) AT1 receptor is involved in development of hypertension and cardiac fibrosis via modifying ACE2 activity, eNOS expression and CD44-hyaluronan interaction. Main methods: Male Sprague-Dawley rats were subjected to Ang II infusion (500ng/kg/min) using osmotic minipumps up to 4weeks and the AT1 receptor blocker, telmisartan was administered by gastric gavage (10mg/kg/day) during Ang II infusion. Key findings: Our results indicated that Ang II enhances AT1 receptor, downregulates AT2 receptor, ACE2 activity and eNOS expression, and increases CD44 expression and hyaluronidase activity, an enzyme for hyaluronan degradation. Further analyses revealed that Ang II increases blood pressure and augments vascular/interstitial fibrosis. Comparison of the Ang II group, treatment with telmisartan significantly increased ACE2 activity and eNOS expression in the intracardiac vessels and intermyocardium. These changes occurred in coincidence with decreased blood pressure. Furthermore, the locally-expressed AT1 receptor was downregulated, as evidenced by an increased ratio of the AT2 over AT1 receptor (1.4±0.4% vs. 0.4±0.1% in Ang II group, P&lt;0.05). Along with these modulations, telmisartan inhibited membrane CD44 expression and hyaluronidase activity, decreased populations of macrophages and myofibroblasts, and reduced expression of TGFβ1 and Smads. Collagen I synthesis and tissue fibrosis were attenuated as demonstrated by the less extensive collagen-rich area. Significance: These results suggest that the AT1 receptor is involved in development of hypertension and cardiac fibrosis. Selective activating ACE2/eNOS and inhibiting CD44/HA interaction might be considered as the therapeutic targets for attenuating Ang II induced deleterious cardiovascular effects. 

Retracted: No

PubPeer comments:
 Fig 6B.  Macrophage accumulation, TGFu03b21 expression and myofibroblast proliferation during Ang II infusion. ... TGFu03b21 expression (B) was analyzed by Western blot. All bands were normalized by actin as illustrated at 2 and 4 weeks, respectively. ![file] Fig 5 from [Zhang et al (2015)] .  Effects of liraglutide and linagliptin on expression of TGFu03b21 ... protein. Ang II infusion did not affect expression of TGFu03b21,... at week 2 as normalized by actin for each band, but significantly upregulated TGFu03b21... at week 4, which were significantly inhibited by liraglutide and linagliptin. ![file] , 
 Dear Dr. Camphorifolia: Our lab manager came back yesterday from her vacation. This senior research scientist has been working with me for so many years. She is in charge of original data organization in lab. In all study files, all data are kept by the experimental parameters measured, and then followed by classification of the different studies. When the time is ready for preparing submission, the photos can be inserted from corresponding study folders. I told her what happened on this publication. She found this original blot film immediately from her files for me to review. As you can see, this photo is divided into two parts: A and B. Each individual band represents one animal from different study group (i.e., N=6 each group, Sham (Nor), Ang II (control) and telmisartan (Telmi). It was very clear that scanned band of TGFu03b21 at week 4 in this published article was inserted from a wrong study file folder (i.e, mismatched). I was so ashamed to make such a stupid mistake during figure preparation. Thank you so much to pinot out this error, and I also very much appreciate the time you have spent on reviewing this article. I truly agree that the honesty is a basic character for all scientist who are doing experimental research. Note: I have tried several times for inserting the photo of original bands for all groups in Pubpeer, but it said that the file is too big to insert. I will be pleased if you can let me know your email, so I can send it to you directly. Thank you! My best regards! Zhi-Qing ,