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Cardiac Gene Therapy With Relaxin Receptor 1 Overexpression Protects Against Acute Myocardial Infarction.

ABSTRACT: Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice. Up-regulation of Rxfp1 was confirmed via quantitative polymerase chain reaction, and overexpressing animals showed increased sensitivity to relaxin-induced ventricular inotropic response. Overexpressing animals also demonstrated reduced infarct size and preserved cardiac function 24 hours after ischemia-reperfusion. Up-regulation of RXFP1 via AAV9 vectors has potential therapeutic utility in preventing adverse remodeling after myocardial infarction.

SUBMITTER: Devarakonda T

PROVIDER: S-EPMC8807852 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Cardiac Gene Therapy With Relaxin Receptor 1 Overexpression Protects Against Acute Myocardial Infarction.

Devarakonda Teja T Mauro Adolfo G AG Cain Chad C Das Anindita A Salloum Fadi N FN

JACC. Basic to translational science 20211222 1

Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice. Up-regulation of <i>Rxfp1</i> was confirmed via quantitative polymerase chain reaction ...[more]

PMID: 35128209

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Project description:In this study, we addressed the functional significance of co-operative DNA binding of the cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) in an experimental murine model of acute myocardial infarction (MI). STAT1 knock-in mice expressing a phenylalanine-to-alanine substitution at position 77 in the STAT1 amino-terminal domain were examined for the early clinical effects produced by ligation of the left anterior descending coronary artery (LAD), an established model for MI. The F77A mutation has been previously reported to disrupt amino-terminal interactions between adjacent STAT1 dimers resulting in impaired tetramerization and defective co-operative binding on DNA, while leaving other protein functions unaffected. Our results demonstrate that a loss of STAT1 tetramer stabilization improves survival of adult male mice and ameliorates left ventricular dysfunction in female mice, as determined echocardiographically by an increased ejection fraction and a reduced left intra-ventricular diameter. We found that the ratio of STAT3 to STAT1 protein level was higher in the infarcted tissue in knock-in mice as compared to wild-type (WT) mice, which was accompanied by an enhanced infiltration of immune cells in the infarcted area, as determined by histology. Additionally, RNA sequencing of the infarcted tissue 24 h after LAD ligation revealed an upregulation of inflammatory genes in the knock-in mice, as compared to their WT littermates. Concomitantly, genes involved in oxidative phosphorylation and other metabolic pathways showed a significantly more pronounced downregulation in the infarcted tissue from STAT1F77A/F77A mice than in WT animals. Based on these results, we propose that dysfunctional STAT1 signalling owing to a lack of oligomerisation results in a compensatory increase in STAT3 expression and promotes early infiltration of immune cells in the infarcted area, which has beneficial effects on left ventricular remodelling in early MI following LAD ligation.

Project description:RationaleThioredoxin-interacting protein (Txnip) is a novel molecular target with translational potential in diverse human diseases. Txnip has several established cellular actions including binding to thioredoxin, a scavenger of reactive oxygen species (ROS). It has been long recognized from in vitro evidence that Txnip forms a disulfide bridge through cysteine 247 (C247) with reduced thioredoxin to inhibit the anti-oxidative properties of thioredoxin. However, the physiological significance of the Txnip-thioredoxin interaction remains largely undefined in vivo.ObjectiveA single mutation of Txnip, C247S, abolishes the binding of Txnip with thioredoxin. Using a conditional and inducible approach with a mouse model of a mutant Txnip that does not bind thioredoxin, we tested whether the interaction of thioredoxin with Txnip is required for Txnip's pro-oxidative or cytotoxic effects in the heart.Methods and resultsOverexpression of Txnip C247S in cells resulted in a reduction in ROS, due to an inability to inhibit thioredoxin. Hypoxia (1% O2, 24 h)-induced killing effects of Txnip were decreased by lower levels of cellular ROS in Txnip C247S-expressing cells compared with wild-type Txnip-expressing cells. Then, myocardial ischemic injuries were assessed in the animal model. Cardiomyocyte-specific Txnip C247S knock-in mice had better survival with smaller infarct size following myocardial infarction (MI) compared to control animals. The absence of Txnip's inhibition of thioredoxin promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage induced by MI. Furthermore, an unbiased RNA sequencing screen identified that hypoxia-inducible factor 1 signaling pathway was involved in Txnip C247S-mediated cardioprotective mechanisms.ConclusionTxnip is a cysteine-containing redox protein that robustly regulates the thioredoxin system via a disulfide bond-switching mechanism in adult cardiomyocytes. Our results provide the direct in vivo evidence that regulation of redox state by Txnip is a crucial component for myocardial homeostasis under ischemic stress.

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Cardiac Gene Therapy With Relaxin Receptor 1 Overexpression Protects Against Acute Myocardial Infarction.

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Cardiac Gene Therapy With Relaxin Receptor 1 Overexpression Protects Against Acute Myocardial Infarction.

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