Heat shock protein 47 and venous thrombosis: letting sleeping bears lie

In a recent study published in Science, Thienel et al. [ [1] Thienel M. Muller-Reif J.B. Zhang Z. Ehreiser V. Huth J. Shchurovska K. Kilani B. Schweizer L. Geyer P.E. Zwiebel M. Novotny J. Lusebrink E. Little G. Orban M. Nicolai L. El Nemr S. Titova A. Spannagl M. Kindberg J. Evans A.L. et al. Immobility-associated thromboprotection is conserved across mammalian species from bear to human. Science. 2023; 380: 178-187 Crossref PubMed Scopus (9) Google Scholar ] suggest that downregulation of heat shock protein 47 (HSP47) is thromboprotective in the setting of immobility, evaluating this with experiments performed across a quartet of mammalian species. These findings were covered extensively in the lay and scientific press and led to calls for the development of novel therapeutic HSP47 inhibitors for preventing or treating venous thromboembolism (VTE) [ 2 Abbasi J. What a study of hibernating bears tells us about deep vein thrombosis. JAMA. 2023; 329: 1541-1542 Crossref PubMed Scopus (1) Google Scholar , 3 Muliyil S. Hibernating bears reveal insights into deep-vein thrombosis. Nat Med. 2023; Crossref Scopus (1) Google Scholar , 4 Schattner M. Sleep like a bear. Science. 2023; 380: 133-134 Crossref PubMed Scopus (1) Google Scholar , 5 Martini E. Conserved protective mechanism for venous thromboembolism. Nat Cardiovasc Res. 2023; 2: 419 Crossref Scopus (1) Google Scholar ]. The authors base their study on the key premise that, despite hibernating for 4 to 7 months per year, brown bears (Ursus arctos) appear to be protected from immobility-associated VTE. To identify novel mechanisms that may contribute to this observation, the authors conducted a series of elegant and challenging studies in which they compared samples obtained from active and hibernating bears. They observed that platelets from hibernating brown bears are more resistant to activation than those from their active counterparts. Using a proteomic screen, the authors found significant downregulation of at least 80 proteins in hibernating brown bear platelets, with a 55-fold decrease in HSP47 levels being the most profound [ [1] Thienel M. Muller-Reif J.B. Zhang Z. Ehreiser V. Huth J. Shchurovska K. Kilani B. Schweizer L. Geyer P.E. Zwiebel M. Novotny J. Lusebrink E. Little G. Orban M. Nicolai L. El Nemr S. Titova A. Spannagl M. Kindberg J. Evans A.L. et al. Immobility-associated thromboprotection is conserved across mammalian species from bear to human. Science. 2023; 380: 178-187 Crossref PubMed Scopus (9) Google Scholar ]. HSP47, encoded by the SERPINH1 gene, is a non-functional member of the serine protease inhibitor superfamily and is best known for its role as an intracellular chaperone of procollagen [ [6] Ito S. Nagata K. Roles of the endoplasmic reticulum-resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease. J Biol Chem. 2019; 294: 2133-2141 Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar ].