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| Status |
Public on Jan 13, 2020 |
| Title |
INCREASED HEAT SHOCK PROTEIN 70 EXPRESSION BY CM-695 ASSOCIATES WITH STRONG ANTITROMBOTIC EFFECT WITHOUT INCREASING BLEEDING |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
BACKGROUND
Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. We described that the heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding.
OBJECTIVES
By using murine models, we want to test the hypothesis that overexpressing Hsp70 with CM-695, a dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered.
METHODS
CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration.
RESULTS
Intraperitoneal (i.p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [P=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs. 39.0 minutes (min) in the control group (CG), P=0.008, n≥10] and ferric chloride (OT: 14.7 vs. 9.2 min in the CG, P=0.032, n≥10) models. I.p. 80 mg/kg CM-695 (n≥9) and intravenous 3 mg/kg rivaroxaban (n≥8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs. 7.5 min in the CG, n≥10]. However, this was dramatically increased by rivaroxaban (BT: 30.0 vs. 13.7 min in the CG, P=0.001, n=10).
CONCLUSIONS
CM-695 is a new antithrombotic drug devoid of bleeding risk that may be envisioned as a useful clinical tool.
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| Overall design |
Two groups of 6 mice each were i.p. administered CM-695 (80 mg/kg twice: two and one hour before sacrifice) or vehicle (saline solution once before sacrifice).
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| Contributor(s) |
Hermida J, Allende M, Guruceaga E, Molina E, Lecumberri R, Oyarzabal J |
| Citation(s) |
28837204 |
| Submission date |
Jan 23, 2017 |
| Last update date |
Jan 15, 2020 |
| Contact name |
Jose Hermida |
| E-mail(s) |
jhermida@unav.es
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| Organization name |
CIMA
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| Street address |
Pio XII 55
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| City |
Pamplona |
| ZIP/Postal code |
31008 |
| Country |
Spain |
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| Platforms (1) |
| GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA362894 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE93958_RAW.tar |
100.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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