Journal article
Modulation of miR-29 influences myocardial compliance likely through coordinated regulation of calcium handling and extracellular matrix
Molecular therapy. Nucleic acids, Vol.34, 102081
12/12/2023
DOI: 10.1016/j.omtn.2023.102081
PMCID: PMC10726423
PMID: 38111915
Abstract
MicroRNAs (miRNAs) control the expression of diverse subsets of target mRNAs, and studies have found miRNA dysregulation in failing hearts. Expression of miR-29 is abundant in heart, increases with aging, and is altered in cardiomyopathies. Prior studies demonstrate that miR-29 reduction via genetic knockout or pharmacologic blockade can blunt cardiac hypertrophy and fibrosis in mice. Surprisingly, this depended on specifically blunting miR-29 actions in cardiomyocytes versus fibroblasts. To begin developing more translationally relevant vectors, we generated a novel transgene-encoded miR-29 inhibitor (TuD-29) that can be incorporated into a viral-mediated gene therapy for cardioprotection. Here, we corroborate that miR-29 expression and activity is higher in cardiomyocytes versus fibroblasts and demonstrate that TuD-29 effectively blunts hypertrophic responses in cultured cardiomyocytes and mouse hearts. Furthermore, we found that adeno-associated virus (AAV)–mediated miR-29 overexpression in mouse hearts induces early diastolic dysfunction, whereas AAV:TuD-29 treatment improves cardiac output by increasing end-diastolic and stroke volumes. The integration of RNA sequencing and miRNA-target interactomes reveals that miR-29 regulates genes involved in calcium handling, cell stress and hypertrophy, metabolism, ion transport, and extracellular matrix remodeling. These investigations support a likely versatile role for miR-29 in influencing myocardial compliance and relaxation, potentially providing a unique therapeutic avenue to improve diastolic function in heart failure patients.
Boudreau and colleagues corroborate that miR-29 expression and function is higher in cardiac myocytes versus fibroblasts and promotes cardiomyocyte hypertrophy. In studies in mice, adeno-associated virus 9–mediated miR-29 overexpression impaired diastolic filling and cardiac output (CO), whereas miR-29 inhibition blunted pressure overload–induced hypertrophy and improved diastolic filling and CO.
Details
- Title: Subtitle
- Modulation of miR-29 influences myocardial compliance likely through coordinated regulation of calcium handling and extracellular matrix
- Creators
- Xiaoming Zhang - University of IowaJared M. McLendon - University of IowaBailey D. Peck - University of IowaBiyi Chen - University of IowaLong-Sheng Song - University of IowaRyan L. Boudreau - Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Molecular therapy. Nucleic acids, Vol.34, 102081
- DOI
- 10.1016/j.omtn.2023.102081
- PMID
- 38111915
- PMCID
- PMC10726423
- NLM abbreviation
- Mol Ther Nucleic Acids
- ISSN
- 2162-2531
- eISSN
- 2162-2531
- Publisher
- American Society of Gene & Cell Therapy
- Grant note
- DOI: 10.13039/100000050, name: NHLBI; DOI: 10.13039/100000968, name: American Heart Association Inc
- Language
- English
- Date published
- 12/12/2023
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984532058102771
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