Abstract 495: Calpain Inhibition in Bone Marrow--Derived Cells Attenuates Atherosclerosis but Not Aortic Aneurysms in Hypercholesterolemic Mice Infused With Angiotensin II
Background and Objective: Calpains are calcium-dependent neutral cysteine proteases that are essential for multiple cellular functions such as cytoskeletal remodeling, cell cycle, and apoptosis. Angiotensin II (AngII)-infusion into mice profoundly increased both aortic protein and activity of calpains. In addition, pharmacological inhibition of calpain attenuated AngII-induced aortic medial macrophage accumulation, atherosclerosis, ascending and abdominal aortic aneurysm (AAs) in mice. Using mice that overexpress calpastatin, the endogenous inhibitor of calpains, the purpose of this study was to determine whether calpains in bone marrow-derived cells contribute to AngII-induced atherosclerosis and AAs in hypercholesterolemic mice.
Methods and Results: Bone marrow cells were harvested from either calpastatin (CAST) overexpression transgenic (Tg) or wild type (WT) mice and injected (7.5 x 106 cells/mouse) into age-matched male LDL receptor -/- recipient mice that had been irradiated with a total of 900 Rads from a cesium source. Four weeks after bone marrow repopulation, recipient mice were fed a saturated fat-enriched diet and infused with either saline or AngII (1,000 ng/kg/min) for 4 weeks. The CAST Tg or WT genotypes used for repopulation had no effect on body weight, white blood cell counts and plasma cholesterol concentrations during AngII infusion. Baseline systolic blood pressure was not different, and AngII infusion increased systolic blood pressure equivalently in both genotypes. Ex vivo measurement of maximal diameter of abdominal aorta showed a comparable dilation in WT and Tg mice (1.28 ± 0.11 versus 1.32 ± 0.08 mm, P = NS). Calpain inhibition showed no discernible effects on AngII-induced ascending AA development (11.7 ± 0.47 versus 11.1 ± 0.54 mm2, P = NS). Interestingly, overexpression of CAST in bone marrow-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches by en face measurement (Intimal lesions: WT = 19.9 ± 1.8 % versus Tg = 11.0 ± 1.2 %; n=14, P<0.001).
Conclusion: Calpain inhibition in bone marrow-derived cells attenuates AngII-induced atherosclerosis but does not influence formation of ascending and abdominal AAs in hypercholesterolemic mice.
Author Disclosures: V. Subramanian: None. D. Howatt: None. A. Balakrishnan: None. J. Moorleghen: None. D. Rateri: None. L. Baud: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.