Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice.
Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice.
复制标题
DOI：
10.1161/atvbaha.120.315546
复制
发表时间：
2021-05-05
期刊：
影响因子：
--
通讯作者：
Subramanian V
中科院分区：
文献类型：
--
作者：
Muniappan L;Okuyama M;Javidan A;Thiagarajan D;Jiang W;Moorleghen JJ;Yang L;Balakrishnan A;Howatt DA;Uchida HA;Saido TC;Subramanian V
Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix (ECM) with contractile filaments. During AAA development, (i) aortic medial degeneration is associated with loss of smooth muscle cell (SMC) integrity, and (ii) fibrogenic mesenchymal cells (FMSCs) mediate ECM remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Angiotensin II (AngII)-induced AAAs in low density receptor deficient (LDLR−/−) mice. Here we evaluated the functional contribution of FMSCs-derived calpain-2 on (i) cytoskeletal structural protein and ECM alterations, and (ii) AAA progression. Calpain-2 protein, and cytoskeletal protein (filamin and talin) fragmentation are significantly elevated in human and AngII-induced AAAs in mice. To examine the relative contribution of calpain-2 in AAA development, calpain-2 floxed mice in an LDLr−/− background were bred to mice with a tamoxifen-inducible form of Cre under control of either the ubiquitous promoter, chicken β-actin or FMSC-specific promoter, Col1α2. Ubiquitous or FMSC-specific depletion of calpain-2 in mice suppressed AngII-induced AAAs, filamin/talin fragmentation, while promoting ECM protein, collagen in the aortas. Calpain-2 silencing in aortic SMCs or fibroblasts reduced AngII-induced filamin fragmentation. In addition, silencing of filamin in aortic SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed rupture of established AngII-induced AAAs in mice. Our studies implicate that calpain-2 deficiency prevents (i) AngII-induced cytoskeletal structural protein fragmentation and AAA development, and (ii) stabilize and suppress rupture of established AAAs in mice.
