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Modulation of miR-29 influences myocardial compliance likely through coordinated regulation of calcium handling and extracellular matrix

ABSTRACT: MicroRNAs (miRs) control the expression of diverse subsets of target mRNAs, and studies have found miR dysregulation in failing hearts. Expression of miR-29 is abundant in heart, increased with aging, and 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. Herein, 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 viral (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. Integration of RNA-seq and miR-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE241423 | GEO | 2023/11/21

REPOSITORIES: GEO

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Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy

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2016-11-13 | GSE86882 | GEO

Age-dependent increase of oxidative stress regulates microRNA-29 family preserving cardiac health

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