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The molecular mechanism underlying angiotensin II-induced cardiovascular injury remains to be defined. The present study was undertaken to determine the role of NOTCH1 in the process of angiotensin II-induced cardiac remodeling in vivo.
We compared the in vivo effects of 4 weeks of subcutaneous angiotensin II infusion on wild-type and NOTCH1-deficient mice. Blood pressure was measured by tail-cuff method with a Softron BP system. Echocardiography was used for measurement of cardiac function. Immunohistochemistry, quantitative real-time PCR and western blot were used for detecting the expression of collagen I, collagen III, α-SMA, TGF-β1, CTGF, Smad2/3 and NF-κB/p65 to evaluate the development of cardiac fibrosis and inflammation. Macrophage and T-cell infiltration in left ventricular tissues were measured by immunohistochemistry and quantitative real-time PCR.
4 weeks after angiotensin II infusion, there was no difference in blood pressure between NOTCH1 KO and wild-type mice. The knockout of NOTCH1 significantly attenuated hypertension induced cardiac fibrosis and inflammation. These results were related to the protection against the decrease in LV ejection fraction and increase in LV mass induced by hypertension, the downregulation of cardiac fibrosis markers, including collagen I, collagen III, α-SMA, the absence in macrophage and leukocytic infiltration, the inactivation of the Smad 2/3 and NF-κB signaling pathway in left ventricular tissues. Additional researches in vitro also demonstrated the cardiac fibrosis and inflammation induced by angiotensin II were inhibited in NOTCH1 KO cardiomyocytes through inactivation of Smad2/3 and NF-κB signaling pathway.
NOTCH1 is a positive regulator of cardiac fibrosis and inflammation through facilitating Smad2/3 and NF-κB signaling pathway, which induces hypertensive cardiac remodeling and dysfunction. Modification of NOTCH1 may be a new therapeutic strategy for hypertensive cardiovascular disease.