Novel bisindolylmaleimide derivative inhibits mitochondrial permeability transition pore and protects the heart from reperfusion injury

Abstract

Despite major advances in treating patients with coronary heart disease, reperfusion injury is still considered to be a major problem, especially in surgical settings. Here, we demonstrate the protective effects of a novel bisindolylmaleimide derivative, MS1 (2-[1-(3-aminopropyl)indol-3-yl]-3-(indol-3-yl)-N-methylmaleimide), against reperfusion injury of the heart. After anesthesia and artificial ventilation, Wistar rats were subjected to 30 min of left coronary artery occlusion followed by 120 min of reperfusion with or without treating the rats with MS1 (2.25 mumol.L-1.kg-1) before left coronary artery occlusion. Compared with the untreated hearts, MS1 treatment significantly reduced myocardial infarct size (35.1% +/- 3% vs. 75.5% +/- 5%, p < 0.001), reduced prevalence of apoptotic cells (2.6% +/- 0.5% vs. 12.2% +/- 2.1%, p < 0.001), prevented mitochondrial swelling and cytochrome c release, inhibited downregulation of antiapoptotic protein Bcl-2 expression, and suppressed caspase-3 activation. In contrast, pretreatment with atractyloside, a mitochondrial permeability transition pore opener, abolished the protective effects of MS1. In conclusion, MS1 inhibits pathologic opening of permeability transition pores and protects the heart against reperfusion injury and pathologic apoptosis.

Indolylmaleimide Derivative IM-17 Shows Cardioprotective Effects in Ischemia-Reperfusion Injury

“…We previously developed a bisindolylmaleimide derivative MS-1 (Figure ) from a well-known PKC inhibitor, BM I, and reported that it inhibited necrotic cell death induced by H 2 O 2 through PKC-independent mechanisms. This molecule was also found to reduce the area of myocardial infarction in an in vivo rat ischemia-reperfusion injury model, in which oxidative-stress-induced necrosis is thought to be involved. , This fact suggested that MS-1 could be a novel therapeutic lead. However, MS-1 showed cytotoxicity and inhibitory activities toward several kinases at high concentrations .…”

Engineered Heart Tissue: A Novel Tool to Study the Ischemic Changes of the Heart In Vitro

“…This was further confirmed by the molecular analysis of cell survival Akt and Bcl-2, both of which were downregulated in EHT subjected to hypoxia ( Fig 4 ). Most importantly, treating EHT with pro-survival ACh or CsA [10], [16], markedly inhibited the hypoxia induced damage to the EHT (P<0.01, Fig 3 and 4 ). …”

“…Samples were then embedded with fresh epoxy resin into molds and placed in an 80°C oven for 18 hr. Ultrathin sections were stained with uranyl acetate and lead citrate and were examined under an electron microscope [16].…”

Catalytic Effect of Cesium Cation Adduct Formation on the Decarboxylation of Carboxylate Ions in the Gas Phase

“…The discovery of the simplest bisindolylmaleimide natural product, arcyriarubin A,2 from a slime mold ( Arcyria denudate ) spearheaded the extensive study of this class of compounds, with more than 2400 and 4000 bisindolylmaleimide‐related references in the PubMed and SciFinder databases, respectively. Bisindolylmaleimide analogues, with activities in cancer,3 diabetes,4 and cardiovascular5 and neurodegenerative6 disease models have now been synthesized, some of which have advanced into clinical trials7 (Scheme ). Surprisingly, bisindolylmaleimide biosynthesis has remained uncharacterized.…”