"Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice"

Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice

Latha Muniappan, Michihiro Okuyama, Aida Javidan, Devi Thiagarajan, Weihua Jiang, Jessica J. Moorleghen, Lihua Yang, Anju Balakrishnan, Deborah A. Howatt, Haruhito A. Uchida, Takaomi C. Saido, Venkateswaran Subramanian

Originally published25 Mar 2021https://doi.org/10.1161/ATVBAHA.120.315546Arteriosclerosis, Thrombosis, and Vascular Biology. ;0:ATVBAHA.120.315546

Objective:

Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix with contractile filaments. During abdominal aortic aneurysm (AAA) development, (1) aortic medial degeneration is associated with loss of smooth muscle cell integrity and (2) fibrogenic mesenchymal cells mediate extracellular matrix remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Ang II (angiotensin II)–induced AAAs in LDLR−/− (low-density receptor deficient) mice. Here, we evaluated the functional contribution of fibrogenic mesenchymal cells-derived calpain-2 on (1) cytoskeletal structural protein and extracellular matrix alterations and (2) AAA progression.

Approach and Results:

Calpain-2 protein and cytoskeletal protein (filamin and talin) fragmentation are significantly elevated in human and Ang II–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 fibrogenic mesenchymal cell-specific promoter, Col1α2. Ubiquitous or fibrogenic mesenchymal cell-specific depletion of calpain-2 in mice suppressed Ang II–induced AAAs, filamin/talin fragmentation, while promoting extracellular matrix protein, collagen in the aortas. Calpain-2 silencing in aortic smooth muscle cells or fibroblasts reduced Ang II–induced filamin fragmentation. In addition, silencing of filamin in aortic SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed rupture of established Ang II–induced AAAs in mice.

Conclusions:

Our studies implicate that calpain-2 deficiency prevents (1) Ang II–induced cytoskeletal structural protein fragmentation and AAA development and (2) stabilize and suppress rupture of established AAAs in mice.