Abstract
Although 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.
Highlights
MicroRNA-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
To further validate the expression of miRNA-7 in the cardiomyocytes, adult cardiomyocytes were isolated from NTg and Tg mice. quantitative real time PCR (qRT-PCR) was performed on the mRNA isolated from adult cardiomyocytes that showed significantly higher expression of miRNA-7 in the Tg cardiomyocytes compared to the NTg (Fig. 1b, right panel)
The current study shows that cardiomyocyte expression of miRNA-7 leads to cardiac dilation that bypasses the classical adaptive hypertrophy to increasing mechanical overload
Summary
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. 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. Though studies have focused on determining molecular components involved in the transition from hypertrophy to dilation[3,4], less is known about these pathways Understanding these pathways becomes critical as it is known that anti-cancer therapeutics including those that target epidermal growth factor receptor (anti-ERBB agents) family[5,6] leads to cardiac dilation of the otherwise healthy hearts bypassing the adaptive hypertrophic response[7]. These observations support the role of ERBB2 in adaptive cardiac hypertrophy and consistently, chemotherapeutic targeting of ERBB2 in patients results in cardiac dilation of the otherwise healthy h earts[15]
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