RT Journal Article
SR Electronic
T1 Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.15.043687
DO 10.1101/2020.04.15.043687
A1 Latha Muniappan
A1 Michihiro Okuyama
A1 Aida Javidan
A1 Devi Thiagarajan
A1 Weihua Jiang
A1 Jessica J. Moorleghen
A1 Lihua Yang
A1 Anju Balakrishnan
A1 Deborah A. Howatt
A1 Haruhito A. Uchida
A1 Takaomi C. Saido
A1 Venkateswaran Subramanian
YR 2020
UL http://biorxiv.org/content/early/2020/04/15/2020.04.15.043687.abstract
AB BACKGROUND 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) mediates 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.OBJECTIVES To evaluate the functional contribution of FMSCs-derived calpain-2 on (i) cytoskeletal structural protein and ECM alterations, and (ii) AAA progression.METHODS Calpain-2 protein, and cytoskeletal protein (e.g. filamin or talin) fragmentation in human and mice AAA tissues were assessed by immunohistochemical and western blot analyses. LDLR-/- mice that were either inducible-whole body or FMSC-specific calpain-2 deficient were fed a fat-enriched diet and infused with AngII for 4 weeks. The association of cytoskeletal protein to ECM was evaluated using aortic SMCs, in vitro. In addition, the effect of calpain-2 deficiency on the stability of established AAA was examined.RESULTS Calpain-2 protein, and filamin/talin fragmentation are significantly elevated in AAAs. Ubiquitous or FMSC-specific depletion of calpain-2 suppressed AngII-induced AAAs, filamin/talin fragmentation and promoted ECM protein, collagen. Calpain-2 silencing in SMCs reduced AngII-induced filamin/talin fragmentation. In addition, silencing of filamin or talin in SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed established AAA rupture.CONCLUSION Calpain-2 activation promotes cytoskeletal structural protein fragmentation and ECM degradation of experimental AAA aortas. Treatment with calpain-2 specific inhibitor may facilitate the clinical management of AAA.Competing Interest StatementThe authors have declared no competing interest.AngIIangiotensin IIAAAabdominal aortic aneurysmLDLlow-density lipoproteinECMextracellular matrixSMCsmooth muscle cell