Cardiac overexpression of microRNA-7 is associated with adverse cardiac remodeling

AbstractRole of microRNA-7 (miRNA-7) in targeting Epidermal growth factor receptor (EGFR/ERBB) family is known in dividing cancer cells while less is known about its role in terminally differentiated cardiac cells. We generated transgenic (Tg) mice with cardiomyocyte-specific overexpression of miRNA-7 to determine its role in regulating cardiac function. Despite similar survival, expression of miRNA-7 results in cardiac dilation as measured by echocardiography, instead of age-based cardiac hypertrophy observed in littermate controls. In contrast to the classical adaptive hypertrophy in response to TAC, miRNA-7 Tg mice directly undergo cardiac dilation post-TAC that is associated with increased fibrosis. Interestingly, significant loss in ERBB2 expression was observed in cardiomyocytes with no changes in ERBB1 (EGFR). Gene ontology and cellular component analysis using the cardiac proteomics data showed significant reduction in mitochondrial membrane integrity reflecting the differential enrichment/loss of proteins in miRNA-7 Tg mice compared to littermate controls. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized and rounded mitochondrial morphology indicating mitochondrial dysfunction. These findings show that expression of miRNA-7 uniquely results in cardiac dilation instead of adaptive hypertrophic response to cardiac stress providing insights on adverse remodeling in physiology and pathology.

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Cardiac expression of microRNA-7 is associated with adverse cardiac remodeling

Scientific Reports ◽

10.1038/s41598-021-00778-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Manveen K. Gupta ◽

Anita Sahu ◽

Yu Sun ◽

Maradumane L. Mohan ◽

Avinash Kumar ◽

...

Keyword(s):

Growth Factor Receptor ◽

Significant Loss ◽

Transverse Aortic Constriction ◽

Cardiac Physiology ◽

Aortic Constriction ◽

Hypertrophic Response ◽

Erbb2 Expression ◽

Physiological Cardiac Hypertrophy ◽

Epidermal Growth

AbstractAlthough microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.

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Abstract 120: Epidermal Growth Factor Receptor (EGFR) Family Dimeric Partners Switch During Pathological Stress in microRNA-7 Transgenic Mice

Circulation Research ◽

10.1161/res.117.suppl_1.120 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Manveen Gupta ◽

Xi Wang ◽

Elizabeth Martelli ◽

Sathyamangla V Naga Prasad

Keyword(s):

Cardiac Dysfunction ◽

Biochemical Analysis ◽

Growth Factor Receptor ◽

Aortic Constriction ◽

Human Heart Failure ◽

Hypertrophic Response ◽

Downstream Signaling ◽

Age Dependent ◽

Epidermal Growth ◽

Egfr Family

miRNA-7 is known to target epidermal growth factors receptor 1(EGFR1) in cancer cells. EGFR family members (EGFR 1, 2, 3 and 4) are known to form homo- and/or hetero-dimers to mediate downstream signals . Our previous study in human heart failure (Naga Prasad etal., JBC, 2009) showed that EGFR2 (ERBB2) was targeted by miRNA-7. Based on this study, we developed transgenic (Tg) mice with cardiomyocyte-specific overexpression of miRNA-7. miRNA-7 Tg mice have age dependent deterioration in cardiac dysfunction and is associated with cardiac dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS &12 months - 24%FS) and yet, they survive well for more than a year. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miRNA-7 Tg mice were subjected to transverse aortic constriction (TAC) for two weeks. In contrast to the wild type littermates which undergo hypertrophic response following TAC, miRNA-7 Tg mice have accelerated cardiac dysfunction and dilation within two weeks. Biochemical analysis interestingly showed differential switching of dimeric EGFR partners in hearts of the miRNA-7 Tg mice compared to their sham controls. Our presentation will discuss the differential downstream signaling induced by changing of EGFR dimeric partners induced by pathological stress like TAC in the wildtype and miRNA-7 Tg mice.

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Abstract 464: Dynamic Regulation of the Epidermal Growth Factor Receptor Protein Interactome via β1-adrenergic Receptor-mediated Transactivation in Cardiomyocytes

Circulation Research ◽

10.1161/res.127.suppl_1.464 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Jeanette Einspahr

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Mitochondrial Function ◽

Adrenergic Receptor ◽

Growth Factor Receptor ◽

Neonatal Rat ◽

Mitochondrial Morphology ◽

Epidermal Growth ◽

The Impact

Heart Failure (HF) is a chronic, progressive condition wherein the heart cannot perfuse adequate amounts of blood and oxygen to meet the demands of metabolizing tissues. Gold standard HF therapeutics currently consist of a small repertoire of neurohormone modulators that still result in ~50% mortality within 5 years. Our ongoing goal is to develop new signaling modalities as refined HF therapeutics. We have shown that β1-adrenergic receptor (β1AR) stimulation rapidly induces epidermal growth factor receptor (EGFR)-dependent protein signaling responses in various regions of cardiomyocytes (CM). We hypothesize that differences in the subcellular localization and protein interactomes of EGFR following differential ligand stimulation modulate CM functions in distinct manners. To test this, we infected neonatal rat ventricular myocytes (NRVM) with adenoviruses encoding HA-β1AR and Flag-EGFR, stimulated them with vehicle, isoproterenol or EGF for 5 min and performed mass spectroscopy analysis of the Flag-EGFR immunoprecipitates. While hundreds of protein interactions were identified, one of the highly enriched subcellular groups belonged to mitochondrial proteins, for which there is no information regarding the role of EGFR in their regulation in CM. Via fractionation and digestion analyses, we have confirmed EGFR localization to the outer mitochondrial membrane in CM and have begun to assess the impact of EGFR on mitochondrial function. Transmission electron microcopy analysis of mitochondrial morphology show that CM-specific EGFR knockdown (CM-EGFR-KD) increases mitochondrial circularity and mitochondria/area without changes in other parameters including perimeter or cristae density, suggesting altered bioenergetic potential. Indeed, extracellular flux (Seahorse) analysis of CM-EGFR-KD versus control CM revealed that CM-EGFR-KD increased maximal and reserve capacities and a trend toward increased ATP production. Elucidating the mechanism(s) of EGFR localization to and association with proteins at CM mitochondria, as well as its impact on mitochondrial function normally or in response to catecholamine stimulation will provide insight into the potential utility of targeting mitochondrial EGFR to improve HF outcomes.

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