Abstract
Activation of the renin-angiotensin system (RAS) is associated with hypertension and heart disease. However, how RAS activation causes cardiac lesions remains elusive. Here we report the involvement of Wnt/β-catenin signaling in this process. In rats with chronic infusion of angiotensin II (Ang II), eight Wnt ligands were induced and β-catenin activated in both cardiomyocytes and cardiac fibroblasts. Blockade of Wnt/β-catenin signaling by small molecule inhibitor ICG-001 restrained Ang II-induced cardiac hypertrophy by normalizing heart size and inhibiting hypertrophic marker genes. ICG-001 also attenuated myocardial fibrosis and inhibited α-smooth muscle actin, fibronectin and collagen I expression. These changes were accompanied by a reduced expression of atrial natriuretic peptide and B-type natriuretic peptide. Interestingly, ICG-001 also lowered blood pressure induced by Ang II. In vitro, Ang II induced multiple Wnt ligands and activated β-catenin in rat primary cardiomyocytes and fibroblasts. ICG-001 inhibited myocyte hypertrophy and Snail1, c-Myc and atrial natriuretic peptide expression, and abolished the fibrogenic effect of Ang II in cardiac fibroblasts. Finally, recombinant Wnt3a was sufficient to induce cardiomyocyte injury and fibroblast activation in vitro. Taken together, these results illustrate an essential role for Wnt/β-catenin in mediating hypertension, cardiac hypertrophy and myocardial fibrosis. Therefore, blockade of this pathway may be a novel strategy for ameliorating hypertensive heart disease.
Highlights
Heart failure is becoming a public healthcare burden on a global scale[1,2]
angiotensin II (Ang II) infusion, which is characterized by hypertension, cardiac hypertrophy and fibrosis[15], to investigate the mechanism underlying cardiac hypertrophy
To study a possible connection between cardiac hypertrophy and Wnt/β-catenin signaling, we carried out a comprehensive analysis of the mRNA expression of all Wnt ligands in the heart after Ang II infusion
Summary
Heart failure is becoming a public healthcare burden on a global scale[1,2]. Approximately 38 million people are diagnosed as heart failure. The heart often responds with hypertrophic growth, characterized by increasing myocytes size and cardiac wall thickness, in various pathologic conditions, such as hypertension, myocardial infarction, chronic ischemia and valvular disease[4]. This growth in heart size may initially be adaptive or compensatory, mounting studies point out that sustained cardiac hypertrophy is an independent risk factor for heart failure. Pathologic hypertrophy is often accompanied by an increased expression of non-contractile proteins, such as collagens and fibronectin[8,9] This leads to myocardial fibrosis, diastolic dysfunction, and eventually heart failure. Our studies suggest that inhibition of Wnt/β-catenin signaling may be a novel and effective strategy for therapeutic intervention of hypertensive heart disease
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