# A novel therapeutic peptide to inhibit reperfusion injury during acute myocardial infarction

Prisca Boisguérin, Aurélie Covinhes, Laura Gallot, Christian Barrere, Anne

Vincent, Christophe Piot, Joël Nargeot, Stéphanie Barrère-Lemaire

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Prisca Boisguérin, Aurélie Covinhes, Laura Gallot, Christian Barrere, Anne Vincent, et al. A novel therapeutic peptide to inhibit reperfusion injury during acute myocardial infarction. meeting of the Southeast Asian section of the International Society for Heart Research World, ISHR-SEA, Oct 2024, Singapour, Singapore. pp.100173, 10.1016/j.jmccpl.2024.100173. hal-05402245

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Journal of Molecular and Cellular Cardiology
Plus

Volume 10, Supplement 2, December 2024, 100173

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10051: A novel therapeutic peptide to
inhibit reperfusion injury during acute
myocardial infarction

Prisca Boisguérin, Aurélie Covinhes, Laura Gallot, Christian Barrere, Anne Vincent, Christophe Piot, Joël Nargeot, Stéphanie Barrère-Lemaire

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**Methods:** A total of 40 cases were selected and grouped into Diabetic cardiomyopathy with Ischemic changes (DCI), Diabetic subjects with cardiomyopathy (DCM) and without cardiomyopathy (DM). The expression of EndMT marker genes (Snail, E-Cadherin, N-Cadherin) and localization of mesenchymal marker FSP-1 and fibrotic marker genes (TGF-β) were assessed along with MMPs (MMP-2, MMP-9, TIMP-1).

**Results:** We re-established that endothelial cells downregulate the expression of cell junction proteins during EndMT similar to epithelial-mesenchymal transition (EMT). The downregulation of E-cadherin destabilizes adherens junctions in EndMT, balanced by increased expression of N-cadherin. This results in a 'cadherin switch' that alters cell adhesion and is a hallmark of both EndMT and EMT. Similarly, SNAIL transcription factors are induced by TGF-β in EndMT and considered as downstream EndMT effectors. In addition to these markers, TGF-β found to be function as the EndMT inducers. The presence of both endothelial and mesenchymal marker in the cardiomyocytes is a suggestive feature of EndMT. Hence, our results suggested that endothelial cells of cardiac tissue undergo a series of molecular event that leads to the change in fate of EndMT.

**Conclusions:** Fibrotic gene markers have an important role in cardiac fibrosis and EndMT. It may be used as a prognostic indicator in cardiac remodelling post myocardial infarction in patients with DCI and DM with cardiomyopathy.

Journal of Molecular and Cellular Cardiology Plus 10S2 (2024) 100172
https://doi.org/10.1016/j.jmccpl.2024.100172

## 10051

### A novel therapeutic peptide to inhibit reperfusion injury during acute myocardial infarction

Prisca Boisguérin<sup>1,2</sup>, Aurélie Covinhes<sup>3,4</sup>, Laura Gallot<sup>1,3,4</sup>, Christian Barrere<sup>3,4</sup>, Anne Vincent<sup>3,4</sup>, Christophe Piot<sup>1,3,4</sup>, Joël Nargeot<sup>1,3,4</sup>, Stéphanie Barrère-Lemaire<sup>1,3,4</sup>

<sup>1</sup>ApoRepair SAS, Montpellier, France; <sup>2</sup>PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France; <sup>3</sup>IGF, University of Montpellier, CNRS, INSERM, Montpellier, France; <sup>4</sup>LabEx ICST, University of Nice, Sophia Antipolis, France

**Background:** Apoptosis is one of the main factors contributing to reperfusion injury after acute myocardial infarction. In this context, we were the first to evidence that the interaction between DAXX (death-associated protein adaptor protein) and FAS receptor plays a major role in reperfusion injury. The aim of our study was to evaluate the cardioprotective effects of the anti-apoptotic peptide Tat-DAXXp interfering with the FAS:DAXX pathway.

**Methods:** Anesthetized mice were subjected to a surgical protocol of reversible coronary artery ligation and treated with Tat-DAXXp at the onset of reperfusion (IV injection). In the first cohort, cardiac injury was evaluated through infarct size measurement (TTC method) and apoptosis quantification (DNA fragmentation and Western blotting). In a second one, mice were followed up for 6 months to evaluate plasma cTnl levels, cardiac function by echocardiography (Vevo1100; Visualsonic), and postmortem myocardial fibrosis (red picrosirius staining).

**Results:** A dose-response study allowed us to identify 1 mg/kg as the optimal dose of Tat-DAXXp providing a 48%-decrease in infarct size after 24 hours of reperfusion. The temporal time window of cardioprotection was defined as the first 30 minutes after the onset of reperfusion. A SPECT-CT study with an iodinated Tat-DAXXp isoform revealed that the therapeutic peptide was completely degraded and eliminated within 24 hours thereby reducing risks of potential side effects. Importantly, immediate post-infarction mortality was reduced by 67% by Tat-DAXXp treatment. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, a decreased amount of cardiac fibrosis (-54%), an improvement of cardiac systolic

function, and the prevention of LV remodeling after 6 months of reperfusion.

**Conclusions:** Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to strong cardioprotection in vivo by inhibiting ischemia-reperfusion injury, preventing cardiac remodeling, and restoring cardiac function.

Journal of Molecular and Cellular Cardiology Plus 10S2 (2024) 100173
https://doi.org/10.1016/j.jmccpl.2024.100173

## 10052

### GPR146 Depletion in Adipose Tissue Protects against Hepatic Steatosis

Yu Shi<sup>1</sup>, Kaiyan Cheng<sup>1</sup>, Thi Tun Thi<sup>1</sup>, Yang Yang<sup>1</sup>, Yifan Wang<sup>1</sup>, Vanna Chhay<sup>1</sup>, Yujia Shen<sup>1</sup>, Haojie Yu<sup>1</sup>

<sup>1</sup>National University of Singapore, Yong Loo Lin School of Medicine

**Background:** The lack of therapies for nonalcoholic fatty liver disease (NAFLD) despite a worldwide prevalence highlights the urgent need for a better understanding of its etiology.

**Methods and Results:** Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) gene locus is associated with altered circulating liver inflammation enzyme levels in human. Moreover, we found that global or adipocyte-specific depletion of GPR146 in mice protects against diet-induced fatty liver and obesity. Mechanistic studies of GPR146's molecular function reveal that it promotes CEBP-PPARγ signaling activity through activation of Gαq-PKC signaling pathway, thereby regulating adipogenesis in preadipocytes.

**Conclusions:** Taken together, these findings outline a regulatory role of GPR146/PKC axis in regulating liver lipid metabolism through adipose-liver crosstalk and suggest that GPR146 inhibition could be an effective strategy to treat NAFLD.

Journal of Molecular and Cellular Cardiology Plus 10S2 (2024) 100174
https://doi.org/10.1016/j.jmccpl.2024.100174

## 10053

### Investigating kinetics of therapeutic extracellular vesicle uptake and retention by human IPSC-derived cardiomyocytes following hypoxia/reoxygenation injury

Dora Livkisa<sup>1</sup>, An Pham Dang<sup>1</sup>, Patrick CH Hsieh<sup>2</sup>, David J. Lundy<sup>1</sup>

<sup>1</sup>College of Biomedical Engineering, Taipei Medical University, Taiwan;

<sup>2</sup>Institute of Biomedical Sciences, Academia Sinica, Taiwan

**Background:** Many studies have demonstrated therapeutic benefits of extracellular vesicles (EVs) from a wide variety of cells following myocardial infarction (MI). However, EV delivery, uptake and retention by the heart is poor; typically less than 1% are retained at 1 hour following intravenous injection. Most in vitro models of hypoxic CM protection use long EV incubation/exposure times of 24, 48 or 72 hours, which does not reflect the in vivo reality. Here, we sought to investigate kinetics of EV internalisation, speed of activity onset, and duration of action following a short EV exposure.

**Methods:** iPSC-derived CMs (iCMs) were metabolically matured, then subjected to hypoxia followed by reoxygenation (H/R) to simulate MI. To reflect in vivo exposure to EVs, iCMs were incubated with amniotic fluid MSC-EVs (0.1 mg/ml) for up to 2 hours post-H/R. MSC-EVs were covalently labelled with AF680 and their internalisation was measured at various time points following incubation. iCM gene expression levels of known MSC-EV miRNA target genes were measured at each timepoint to investigate the speed of MSC-EV activity onset, and the duration of MSC-EV influence. Longitudinal measurements of LDH