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Cardiac patch treatment alleviates ischemic cardiomyopathy correlated with unloading pathological stretch and reverting Piezo1/2 expression in left ventricular myocardium

ABSTRACT: Pathologically elevated mechanical load promotes the adverse remodeling of left ventricle (LV) post myocardial infarction, which results in the progression from ischemic cardiomyopathy to heart failure. Cardiac patches could attenuate adverse LV remodeling by providing mechanical support to infarcted and border zone myocardium. However, the mechanism of the translation from mechanical effects to favorable therapeutic outcome is still not clear. This study aims to strengthen the foundation of the theory of cardiac patch treatment. By transcriptome analysis, we found that the myocardial transcription levels of mechanosensitive ion channel proteins Piezo1 and Piezo2 significantly increased in patients with ischemic cardiomyopathy. In vitro tensile tests with local tissue information and finite element modeling revealed a significant decrease in local strain and mechanical load in rat infarcts and sheep LV. Cardiac function and geometry were preserved compared to non-treated control. Further, in LV myocardium of the patch-treated group, MI induced expression levels of Piezo1/2 were significantly reverted to the similar levels of the control group, indicating that Piezo1/2 are key contributors as mechanosensor which initiated the signaling cascade and translated the beneficial mechanical support to therapeutic effects. These findings demonstrated the potential of cardiac patches in treating ICM patients with remodeling risks, and could provide guidance for improvement in next generation of patch devices.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE202228 | GEO | 2024/01/01

REPOSITORIES: GEO

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Project description:Engineered cardiac tissues (ECTs) are platforms to investigate cardiomyocyte maturation and functional integration, to evaluate the feasibility of generating implantable tissues for cardiac repair and regeneration, and may be useful models for pharmacology and toxicology bioassays. These ECTs rapidly mature in vitro to acquire the features of functional cardiac muscle and respond to mechanical load with increased proliferation and maturation. ECTs can be generated from various immature cardiac cell sources and little is known regarding the broad changes in regulatory transcript expression that occur in these in vitro tissues during normal maturation and in response to mechanical or pharmacologic interventions. We tested the hypothesis that global ECT gene expression patterns are sensitive to mechanical loading conditions and tyrosine kinase inhibitors, similar to the maturing myocardium. We generated 3D ECTs from day 14.5 rat embryo ventricular cells, as previously published, and then treated constructs after 5 days in culture for 48 hours with mechanical stretch (5%, 0.5 Hz) and/or the p38MAPK (p38 mitogen-activated protein kinase) selective inhibitor BIRB796. RNA was isolated from 3 sets of experiments and assayed using a standard Agilent rat 4x44k V3 microarray and Pathway Analysis software for transcript expression fold changes and changes in regulatory molecules and networks. At the threshold of a 1.5 fold change in expression, mechanical stretch altered 1,559 transcripts, versus 1,411 for BIRB796, and 1,846 for stretch plus BIRB796. As anticipated, top pathways altered in response to these stimuli include Cellular Development, Cellular Growth and Proliferation; Tissue Development; Cell Death, Cell Signaling, and Small Molecule Biochemistry as well as numerous other pathways. Changes in transcript expression were confirmed by quantitative-PCR for selected regulatory molecules. Thus, ECTs display a broad spectrum of altered gene expression in response to mechanical load and/or tyrosine kinase inhibition, reflecting the complex regulation of proliferation, differentiation, and architectural alignment that occurs during ECT maturation and adaptation. This approach can now be used to test the role of individual molecules and pathways on the regulation of ECT maturation and remodeling. 7 and 4 biological replicates with four groups (control, mechanical stretch, BIRB and mechanical stretch with BIRB)

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Cardiac patch treatment alleviates ischemic cardiomyopathy correlated with unloading pathological stretch and reverting Piezo1/2 expression in left ventricular myocardium

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