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Olmesartan attenuates cardiac remodeling through DLL4/Notch1 pathway activation in pressure overload mice.
J Cardiovasc Pharmacol. 2013 Feb; 61(2):142-51.JC

Abstract

BACKGROUND

Notch1 signaling controls the cardiac adaptation to stress. We therefore aimed to validate whether olmesartan, a widely used angiotensin II type 1 receptor blocker, ameliorates cardiac remodeling and dysfunction via delta-like ligand 4 (DLL4)/Notch1 pathway in mice with chronic pressure overload.

METHODS

Cardiac pressure overload was produced by transverse aortic constriction (TAC). A total of 35 wide-type C57BL/6J mice were randomly divided into sham group, TAC group, TAC + olmesartan group, and TAC + olmsartan + DAPT group (DAPT: γ-secretase inhibitor, Notch signaling inhibitor). Saline (10 mL·kg(-1)·d(-1)) or the same volume of olmesartan liquor (3 mg·kg(-1) d(-1)) was administered by gavage, and DAPT (10 μmole·kg(-1)·d(-1)) by peritoneal injection. After 28 days of treatment, cardiac hemodynamics, echocardiography, and histology were evaluated, followed by quantitative polymerase chain reaction of fetal gene (ANP and SAA) expression. Notch1-related proteins and ERK1/2 were examined by western blot, and the serum level of angiotensin II was determined by means of enzyme-linked immunosorbent assay kits.

RESULTS

Persistent pressure overload-induced left ventricular hypertrophy, dysfunction, fibrosis, and microcirculation dysfunction, together with the upregulation of angiotensin II, ERK1/2, and fetal gene expression. By the activation of DLL4/Notch1, olmesartan decreased left ventricular hypertrophy and fibrosis, preserved cardiac function, and improved capillary density and coronary perfusion. All these curative effects were suppressed by pharmacological blockade of Notch signaling with DAPT.

CONCLUSIONS

Our findings identify a heretofore unknown pharmacological mechanism that olmesartan improves cardiac remodeling and function via DLL4/Notch1 pathway activation in mice with chronic pressure overload, which may present a new therapeutic target for hypertension.

Authors+Show Affiliations

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Validation Study

Language

eng

PubMed ID

23188126

Citation

You, Jieyun, et al. "Olmesartan Attenuates Cardiac Remodeling Through DLL4/Notch1 Pathway Activation in Pressure Overload Mice." Journal of Cardiovascular Pharmacology, vol. 61, no. 2, 2013, pp. 142-51.
You J, Wu J, Jiang G, et al. Olmesartan attenuates cardiac remodeling through DLL4/Notch1 pathway activation in pressure overload mice. J Cardiovasc Pharmacol. 2013;61(2):142-51.
You, J., Wu, J., Jiang, G., Guo, J., Wang, S., Li, L., Ge, J., & Zou, Y. (2013). Olmesartan attenuates cardiac remodeling through DLL4/Notch1 pathway activation in pressure overload mice. Journal of Cardiovascular Pharmacology, 61(2), 142-51. https://doi.org/10.1097/FJC.0b013e31827a0278
You J, et al. Olmesartan Attenuates Cardiac Remodeling Through DLL4/Notch1 Pathway Activation in Pressure Overload Mice. J Cardiovasc Pharmacol. 2013;61(2):142-51. PubMed PMID: 23188126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Olmesartan attenuates cardiac remodeling through DLL4/Notch1 pathway activation in pressure overload mice. AU - You,Jieyun, AU - Wu,Jian, AU - Jiang,Guoliang, AU - Guo,Jing, AU - Wang,Shijun, AU - Li,Lei, AU - Ge,Junbo, AU - Zou,Yunzeng, PY - 2012/11/29/entrez PY - 2012/11/29/pubmed PY - 2013/7/23/medline SP - 142 EP - 51 JF - Journal of cardiovascular pharmacology JO - J Cardiovasc Pharmacol VL - 61 IS - 2 N2 - BACKGROUND: Notch1 signaling controls the cardiac adaptation to stress. We therefore aimed to validate whether olmesartan, a widely used angiotensin II type 1 receptor blocker, ameliorates cardiac remodeling and dysfunction via delta-like ligand 4 (DLL4)/Notch1 pathway in mice with chronic pressure overload. METHODS: Cardiac pressure overload was produced by transverse aortic constriction (TAC). A total of 35 wide-type C57BL/6J mice were randomly divided into sham group, TAC group, TAC + olmesartan group, and TAC + olmsartan + DAPT group (DAPT: γ-secretase inhibitor, Notch signaling inhibitor). Saline (10 mL·kg(-1)·d(-1)) or the same volume of olmesartan liquor (3 mg·kg(-1) d(-1)) was administered by gavage, and DAPT (10 μmole·kg(-1)·d(-1)) by peritoneal injection. After 28 days of treatment, cardiac hemodynamics, echocardiography, and histology were evaluated, followed by quantitative polymerase chain reaction of fetal gene (ANP and SAA) expression. Notch1-related proteins and ERK1/2 were examined by western blot, and the serum level of angiotensin II was determined by means of enzyme-linked immunosorbent assay kits. RESULTS: Persistent pressure overload-induced left ventricular hypertrophy, dysfunction, fibrosis, and microcirculation dysfunction, together with the upregulation of angiotensin II, ERK1/2, and fetal gene expression. By the activation of DLL4/Notch1, olmesartan decreased left ventricular hypertrophy and fibrosis, preserved cardiac function, and improved capillary density and coronary perfusion. All these curative effects were suppressed by pharmacological blockade of Notch signaling with DAPT. CONCLUSIONS: Our findings identify a heretofore unknown pharmacological mechanism that olmesartan improves cardiac remodeling and function via DLL4/Notch1 pathway activation in mice with chronic pressure overload, which may present a new therapeutic target for hypertension. SN - 1533-4023 UR - https://www.unboundmedicine.com/medline/citation/23188126/Olmesartan_attenuates_cardiac_remodeling_through_DLL4/Notch1_pathway_activation_in_pressure_overload_mice_ DB - PRIME DP - Unbound Medicine ER -