Search

Angiotensin II (AngII) has a crucial role in cardiovascular pathologies, including endothelial inflammation and premature vascular aging. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. Here, we have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence assessed by senescence-associated β galactosidase activity. The number of β galactosidase-positive ECs induced by AngII was attenuated by treatment with a senolytic drug ABT737 or the chemical chaperone 4-phenylbutyrate. Monocyte adhesion assay revealed that the pro-inflammatory phenotype in ECs induced by AngII was alleviated by these treatments. AngII stimulation also increased mitochondrial fission in ECs, which was mitigated by mitochondrial division inhibitor-1. Pretreatment with mitochondrial division inhibitor-1 attenuated AngII-induced senescence and monocyte adhesion in ECs. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases., Competing Interests: The authors declare no conflict of interest.

Angiotensin II (AngII)-activated epidermal growth factor receptor has been implicated in abdominal aortic aneurysm (AAA) development. In vascular smooth muscle cells (VSMCs), AngII activates epidermal growth factor receptor via a metalloproteinase, ADAM17 (a disintegrin and metalloproteinase domain 17). We hypothesized that AngII-dependent AAA development would be prevented in mice lacking ADAM17 in VSMCs. To test this concept, control and VSMC ADAM17-deficient mice were cotreated with AngII and a lysyl oxidase inhibitor, β-aminopropionitrile, to induce AAA. We found that 52.4% of control mice did not survive because of aortic rupture. All other surviving control mice developed AAA and demonstrated enhanced expression of ADAM17 in the AAA lesions. In contrast, all AngII and β-aminopropionitrile-treated VSMC ADAM17-deficient mice survived and showed reduction in external/internal diameters (51%/28%, respectively). VSMC ADAM17 deficiency was associated with lack of epidermal growth factor receptor activation, interleukin-6 induction, endoplasmic reticulum/oxidative stress, and matrix deposition in the abdominal aorta of treated mice. However, both VSMC ADAM17-deficient and control mice treated with AngII and β-aminopropionitrile developed comparable levels of hypertension. Treatment of C57Bl/6 mice with an ADAM17 inhibitory antibody but not with control IgG also prevented AAA development. In conclusion, VSMC ADAM17 silencing or systemic ADAM17 inhibition seems to protect mice from AAA formation. The mechanism seems to involve suppression of epidermal growth factor receptor activation., (© 2017 American Heart Association, Inc.)

It has been proposed that membrane microdomains, caveolae, in vascular cells are critical for signal transduction and downstream functions induced by angiotensin II (AngII). We have tested our hypothesis that caveolin-1 (Cav1), a major structural protein of vascular caveolae, plays a critical role in the development of vascular remodeling by AngII via regulation of epidermal growth factor receptor and vascular endothelial adhesion molecule-1. Cav1 -/- and control Cav +/+ mice were infused with AngII for 2 weeks to induce vascular remodeling and hypertension. On AngII infusion, histological assessments demonstrated medial hypertrophy and perivascular fibrosis of aorta and coronary and renal arteries in Cav1 +/+ mice compared with sham-operated Cav1 +/+ mice. AngII-infused Cav1 +/+ mice also showed a phenotype of cardiac hypertrophy with increased heart weight to body weight ratio compared with control Cav1 +/+ mice. In contrast, Cav1 -/- mice infused with AngII showed attenuation of vascular remodeling but not cardiac hypertrophy. Similar levels of AngII-induced hypertension were found in both Cav1 +/+ and Cav1 -/- mice as assessed by telemetry. In Cav1 +/+ mice, AngII enhanced tyrosine-phosphorylated epidermal growth factor receptor staining in the aorta, which was attenuated in Cav1 -/- mice infused with AngII. Enhanced Cav1 and vascular endothelial adhesion molecule-1 expression was also observed in aorta from AngII-infused Cav1 +/+ mice but not in Cav1 -/- aorta. Experiments with vascular cells further provided a potential mechanism for our in vivo findings. These data suggest that Cav1, and presumably caveolae, in vascular smooth muscle and the endothelium plays a critical role in vascular remodeling and inflammation independent of blood pressure or cardiac hypertrophy regulation., (© 2016 American Heart Association, Inc.)

Angiotensin II (AngII)-activated epidermal growth factor receptor has been implicated in abdominal aortic aneurysm (AAA) development. In vascular smooth muscle cells (VSMCs), AngII activates epidermal growth factor receptor via a metalloproteinase, ADAM17 (a disintegrin and metalloproteinase domain 17). We hypothesized that AngII-dependent AAA development would be prevented in mice lacking ADAM17 in VSMCs. To test this concept, control and VSMC ADAM17-deficient mice were cotreated with AngII and a lysyl oxidase inhibitor, β-aminopropionitrile, to induce AAA. We found that 52.4% of control mice did not survive because of aortic rupture. All other surviving control mice developed AAA and demonstrated enhanced expression of ADAM17 in the AAA lesions. In contrast, all AngII and β-aminopropionitrile-treated VSMC ADAM17-deficient mice survived and showed reduction in external/internal diameters (51%/28%, respectively). VSMC ADAM17 deficiency was associated with lack of epidermal growth factor receptor activation, interleukin-6 induction, endoplasmic reticulum/oxidative stress, and matrix deposition in the abdominal aorta of treated mice. However, both VSMC ADAM17-deficient and control mice treated with AngII and β-aminopropionitrile developed comparable levels of hypertension. Treatment of C57Bl/6 mice with an ADAM17 inhibitory antibody but not with control IgG also prevented AAA development. In conclusion, VSMC ADAM17 silencing or systemic ADAM17 inhibition seems to protect mice from AAA formation. The mechanism seems to involve suppression of epidermal growth factor receptor activation. [ABSTRACT FROM AUTHOR]