Male ApoE−/−/C57BL/6J mice or wild type C57BL/6J mice at 10–12 wk of age were obtained from the Jackson Laboratory, Bar Harbor, Maine, and housed at the Stanford Animal Facility, Stanford, CA. Animal care and experimental procedures were conducted in compliance with Stanford Laboratory Animal Care Guidelines. The Administrative Panel on Laboratory Animal Care at Stanford University approved all procedures involving mice.
Two mechanistically distinct, but complementary mouse AAA models were used in this study: subcutaneous Ang II infusion in ApoE−/− mice (Ang II/ApoE−/− model) and intra-aortic PPE infusion in C57BL/6J mice (PPE model). In most experiments, ApoE−/− mice were fed chow supplemented with irbesartan (50 mg/kg), telmisartan (10 mg/kg) or bosentan (100 mg/kg), or were daily given drinking water supplemented with fluvastatin (40 mg/kg) or doxycycline (100 mg/kg). As controls, separate groups of ApoE−/− mice for individual experiments were given the standard chow and drinking water without drug supplementation. One week later, to induce AAAs, all mice were subcutaneously implanted with osmotic minipumps (Alzet model 2004, Durect Corporation, Cupertino, CA) for continuous infusion of Ang II at 1000 ng/kg/min, and treated continuously with their respective drugs for 28 days [9] (link). In additional experiments, C57BL/6J mice were fed telmisartan-supplemented chow (10 mg/kg) or the standard chow. One week thereafter, AAAs were created by transient intra-aortic infusion of PPE as described previously [93] (link), and these mice were continuously fed with the chow with or without telmisartan supplementation for additional 2 wk. In all experiments, doses for two ARBs and bosentan were selected based on published mouse studies in which each drug lowered blood pressure and/or suppressed cardiovascular pathology [94] (link)–[96] (link).
Two mechanistically distinct, but complementary mouse AAA models were used in this study: subcutaneous Ang II infusion in ApoE−/− mice (Ang II/ApoE−/− model) and intra-aortic PPE infusion in C57BL/6J mice (PPE model). In most experiments, ApoE−/− mice were fed chow supplemented with irbesartan (50 mg/kg), telmisartan (10 mg/kg) or bosentan (100 mg/kg), or were daily given drinking water supplemented with fluvastatin (40 mg/kg) or doxycycline (100 mg/kg). As controls, separate groups of ApoE−/− mice for individual experiments were given the standard chow and drinking water without drug supplementation. One week later, to induce AAAs, all mice were subcutaneously implanted with osmotic minipumps (Alzet model 2004, Durect Corporation, Cupertino, CA) for continuous infusion of Ang II at 1000 ng/kg/min, and treated continuously with their respective drugs for 28 days [9] (link). In additional experiments, C57BL/6J mice were fed telmisartan-supplemented chow (10 mg/kg) or the standard chow. One week thereafter, AAAs were created by transient intra-aortic infusion of PPE as described previously [93] (link), and these mice were continuously fed with the chow with or without telmisartan supplementation for additional 2 wk. In all experiments, doses for two ARBs and bosentan were selected based on published mouse studies in which each drug lowered blood pressure and/or suppressed cardiovascular pathology [94] (link)–[96] (link).
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