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1.
Mol Ther ; 31(6): 1807-1828, 2023 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-37073128

RESUMO

While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.


Assuntos
Insuficiência Cardíaca , MicroRNAs , Animais , Camundongos , Células Endoteliais/metabolismo , Insuficiência Cardíaca/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/genética
2.
Mol Ther ; 30(6): 2257-2273, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35278675

RESUMO

As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density, and preserved cardiac ejection fraction. We were able to maximally rescue microvascular and cardiac function with very low doses of antagomir, which specifically silences miR-200c-3p expression in non-myocyte cells. Our results reveal vesicle transfer of miR-200c-3p from cardiomyocytes to cardiac endothelial cells, underlining the importance of cardiac intercellular communication in the pathophysiology of heart failure.


Assuntos
Vesículas Extracelulares , MicroRNAs , Animais , Comunicação Celular , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo
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