Delayed, oral pharmacological inhibition of calpains attenuates adverse post-infarction remodelling

Marcos Poncelas, Javier Inserte, David Aluja, Victor Hernando, Ursula Vilardosa, David Garcia-Dorado

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

© The Author 2017. Aims To determine whether delayed oral administration of the calpain inhibitor SNJ-1945 reduces adverse myocardial remodelling and dysfunction following transient coronary occlusion.Methods and results Male SpragueDawley rats were subjected to 30 min of ischemia followed by 21 days of reperfusion and received the calpain inhibitor SNJ-1945 intraperitoneally at the onset of reperfusion (Acute group), orally starting after 24 h of reperfusion and for 14 days (Chronic group), or the combination of both treatments.Calpain-1 and calpain-2 protein content increased and correlated with higher calpain activity in control hearts.Administration of SNJ-1945 attenuated calpain activation, and reduced scar expansion, ventricular dilation and dysfunction in both acute and chronic groups.Acute treatment reduced infarct size in hearts reperfused for 24 h and inflammation measured after 3 days.Delayed, chronic oral administration of SNJ-1945 attenuated inflammation, cardiomyocyte hypertrophy and collagen infiltration in the non-infarcted myocardium at 21 days in correlation with increased levels of IOEB and reduced NF-OEB activation.In cultured fibroblasts, SNJ-1945 attenuated TGF-b1-induced fibroblast activation.Conclusions Our data demonstrate for the first time that long-term calpain inhibition is possible with delayed oral treatment, attenuates adverse post-infarction remodelling, likely through prevention of NF-OEB activation, and may be a promising therapeutic intervention to prevent adverse remodelling and heart failure in patients with acute myocardial infarction.All rights reserved.
Original languageEnglish
Pages (from-to)950-961
JournalCardiovascular Research
Volume113
Issue number8
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • Calpain
  • Ischemia/reperfusion
  • Post-infarction remodelling

Fingerprint Dive into the research topics of 'Delayed, oral pharmacological inhibition of calpains attenuates adverse post-infarction remodelling'. Together they form a unique fingerprint.

Cite this