TY - JOUR
T1 - The BET Protein Inhibitor Apabetalone Rescues Diabetes-induced Impairment of Angiogenic Response by Epigenetic Regulation of Thrombospondin-1
AU - Mohammed, Shafeeq Ahmed
AU - Albiero, Mattia
AU - Ambrosini, Samuele
AU - Gorica, Era
AU - Karsai, Gergely
AU - Caravaggi, Carlo Maria
AU - Masi, Stefano
AU - Camici, Giovanni Giacomo
AU - Wenzl, Florian
AU - Calderone, Vincenzo
AU - Madeddu, Paolo
AU - Sciarretta, Sebastiano
AU - Matter, Christian M
AU - Spinetti, Gaia
AU - Luscher, Thomas Felix
AU - Ruschitzka, Frank
AU - Costantino, Sarah
AU - Fadini, Gian Paolo
AU - Paneni, Francesco
PY - 2021/12/16
Y1 - 2021/12/16
N2 - AIMS: Therapeutic modulation of blood vessel growth holds promise for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely posttranslational histone modifications, participate in angiogenic response suggesting that chromatin-modifying drugs could be beneficial in this setting. Apabetalone (APA), a selective inhibitor of bromodomain (BRD) and extra-terminal (BET) proteins, prevents BRD4 interactions with chromatin thus modulating transcriptional programs in different organs. We sought to investigate whether APA affects angiogenic response in diabetes.RESULTS: As compared to vehicle, APA restored tube formation and migration in human aortic endothelial cells (HAECs) exposed to high glucose (HG) levels. Expression profiling of angiogenesis genes showed that APA prevents HG-induced upregulation of the anti-angiogenic molecule Thrombospondin-1 (THBS1). ChIP-seq and chromatin immunoprecipitation (ChIP) assays in HG-treated HAECs showed the enrichment of both BRD4 and active marks (H3K27ac) on THBS1 promoter, whereas BRD4 inhibition by APA prevented chromatin accessibility and THBS1 transcription. Mechanistically, we show that THBS1 inhibits angiogenesis by suppressing VEGFA signaling, while APA prevents these detrimental changes. In diabetic mice with hindlimb ischemia, epigenetic editing by APA restored THSB1/VEGFA axis thus improving limb vascularization and perfusion as compared to vehicle-treated animals. Finally, epigenetic regulation of THSB1 by BRD4/H3K27ac was also reported in DM patients with PAD as compared to non-diabetic controls.INNOVATION: This is the first study showing that BET protein inhibition by APA restores angiogenic response in experimental diabetes.CONCLUSIONS: Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in diabetic PAD.
AB - AIMS: Therapeutic modulation of blood vessel growth holds promise for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely posttranslational histone modifications, participate in angiogenic response suggesting that chromatin-modifying drugs could be beneficial in this setting. Apabetalone (APA), a selective inhibitor of bromodomain (BRD) and extra-terminal (BET) proteins, prevents BRD4 interactions with chromatin thus modulating transcriptional programs in different organs. We sought to investigate whether APA affects angiogenic response in diabetes.RESULTS: As compared to vehicle, APA restored tube formation and migration in human aortic endothelial cells (HAECs) exposed to high glucose (HG) levels. Expression profiling of angiogenesis genes showed that APA prevents HG-induced upregulation of the anti-angiogenic molecule Thrombospondin-1 (THBS1). ChIP-seq and chromatin immunoprecipitation (ChIP) assays in HG-treated HAECs showed the enrichment of both BRD4 and active marks (H3K27ac) on THBS1 promoter, whereas BRD4 inhibition by APA prevented chromatin accessibility and THBS1 transcription. Mechanistically, we show that THBS1 inhibits angiogenesis by suppressing VEGFA signaling, while APA prevents these detrimental changes. In diabetic mice with hindlimb ischemia, epigenetic editing by APA restored THSB1/VEGFA axis thus improving limb vascularization and perfusion as compared to vehicle-treated animals. Finally, epigenetic regulation of THSB1 by BRD4/H3K27ac was also reported in DM patients with PAD as compared to non-diabetic controls.INNOVATION: This is the first study showing that BET protein inhibition by APA restores angiogenic response in experimental diabetes.CONCLUSIONS: Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in diabetic PAD.
U2 - 10.1089/ars.2021.0127
DO - 10.1089/ars.2021.0127
M3 - Article
C2 - 34913726
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
SN - 1523-0864
ER -