| RRC ID |
88393
|
| Author |
Kim DH, Beckett JD, Nagpal V, Seman-Senderos MA, Gould RA, Creamer TJ, MacFarlane EG, Chen Y, Bedja D, Butcher JT, Mitzner W, Rouf R, Hata S, Warren DS, Dietz HC.
|
| Title |
Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis.
|
| Journal |
Sci Transl Med
|
| Abstract |
Fibrosis is a common pathologic outcome of chronic disease resulting in the replacement of normal tissue parenchyma with a collagen-rich extracellular matrix produced by myofibroblasts. Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues and diseases, their contribution to fibrosis initiation, maintenance, and progression is thought to be pervasive. Here, we showed that the ability of transforming growth factor-β (TGFβ) to efficiently induce myofibroblast differentiation of cultured epithelial cells, endothelial cells, or quiescent fibroblasts is dependent on the induced expression and activity of dimeric calpains, a family of non-lysosomal cysteine proteases that regulate a variety of cellular events through posttranslational modification of diverse substrates. siRNA-based gene silencing demonstrated that TGFβ-induced mesenchymal transition of a murine breast epithelial cell line was dependent on induction of expression of calpain 9 (CAPN9), an isoform previously thought to be restricted to the gastrointestinal tract. Mice lacking functional CAPN9 owing to biallelic targeting of Capn9 were viable and fertile but showed overt protection from bleomycin-induced lung fibrosis, carbon tetrachloride-induced liver fibrosis, and angiotensin II-induced cardiac fibrosis and dysfunction. A predicted loss-of-function allele of CAPN9 is common in Southeast Asia, with the frequency of homozygosity matching the prediction of Hardy-Weinberg equilibrium. Together with the highly spatially restricted pattern of CAPN9 expression under physiologic circumstances and the heartiness of the murine knockout, these data provide a strong signature for tolerance of therapeutic strategies for fibrosis aimed at CAPN9 antagonism.
|
| Volume |
11(501)
|
| Published |
2019-7-17
|
| DOI |
10.1126/scitranslmed.aau2814
|
| PII |
11/501/eaau2814
|
| PMID |
31316008
|
| PMC |
PMC7351287
|
| MeSH |
Angiotensin II
Animals
Bleomycin
Calcium-Binding Proteins / pharmacology
Calpain / antagonists & inhibitors
Calpain / deficiency
Calpain / genetics
Calpain / metabolism*
Carbon Tetrachloride
Cell Line
Dogs
Epithelial-Mesenchymal Transition*
Fibrosis
Humans
Isoenzymes / metabolism
Liver Cirrhosis / chemically induced
Liver Cirrhosis / prevention & control
Male
Mice, Inbred C57BL
Molecular Targeted Therapy*
Myocardium / enzymology
Myocardium / pathology
Protein Biosynthesis / drug effects
Protein Multimerization / drug effects
RNA Stability / drug effects
Signal Transduction / drug effects
Transforming Growth Factor beta / pharmacology*
|
| IF |
16.304
|
| Resource |
| Mice |
RBRC04790 |
