Revista espanola de cardiologia (English ed.) · 2020
Ischemic dilated cardiomyopathy pathophysiology through microRNA-16-5p.
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Calderon-Dominguez Maria, Mangas Alipio, Belmonte Thalía, Quezada-Feijoo Maribel, Ramos Mónica, Toro Rocío
Аннотация
INTRODUCTION AND OBJECTIVES: The expression levels of microRNA-16-5p (miR-16) are upregulated in ischemic cardiomyopathy and in animal models of ischemic dilated cardiomyopathy (iDCM), inducing myocardial apoptosis. We investigated the role of miR-16 in the adaptive cellular response associated with endoplasmic reticulum (ER) stress and autophagy in the apoptotic iDCM environment.
METHODS: We quantified the miR-16 plasma levels of 168 participants-76 controls, 60 iDCM patients, and 32 familial DCM patients with the pathogenic variant of BAG3-by quantitative real-time polymerase chain reaction and correlated the levels with patient variables. The effects of intracellular miR-16 overexpression were analyzed in a human cardiac cell line. Apoptosis and cell viability were measured, as well as the levels of markers associated with ER stress, cardiac injury, and autophagy.
RESULTS: Plasma miR-16 levels were upregulated in iDCM patients (P=.039). A multivariate logistic regression model determined the association of miR-16 with iDCM clinical variables (P <.001). In vitro, miR-16 overexpression increased apoptosis (P=.02) and reduced cell viability (P=.008). Furthermore, it induced proapoptotic components of ER stress, based on upregulation of the PERK/CHOP pathway. However, we observed augmentation of autophagic flux (P <.001) without lysosomal blockade by miR-16 as a possible cytoprotective mechanism.
CONCLUSIONS: MiR-16 is specifically associated with iDCM. In an ischemic setting, miR-16 activates ER stress and promotes inflammation followed by autophagy in human cardiac cells. Thus, autophagy may be an attempt to maintain cellular homeostasis in response to misfolded/aggregated proteins related to ER stress, prior to apoptosis.
METHODS: We quantified the miR-16 plasma levels of 168 participants-76 controls, 60 iDCM patients, and 32 familial DCM patients with the pathogenic variant of BAG3-by quantitative real-time polymerase chain reaction and correlated the levels with patient variables. The effects of intracellular miR-16 overexpression were analyzed in a human cardiac cell line. Apoptosis and cell viability were measured, as well as the levels of markers associated with ER stress, cardiac injury, and autophagy.
RESULTS: Plasma miR-16 levels were upregulated in iDCM patients (P=.039). A multivariate logistic regression model determined the association of miR-16 with iDCM clinical variables (P <.001). In vitro, miR-16 overexpression increased apoptosis (P=.02) and reduced cell viability (P=.008). Furthermore, it induced proapoptotic components of ER stress, based on upregulation of the PERK/CHOP pathway. However, we observed augmentation of autophagic flux (P <.001) without lysosomal blockade by miR-16 as a possible cytoprotective mechanism.
CONCLUSIONS: MiR-16 is specifically associated with iDCM. In an ischemic setting, miR-16 activates ER stress and promotes inflammation followed by autophagy in human cardiac cells. Thus, autophagy may be an attempt to maintain cellular homeostasis in response to misfolded/aggregated proteins related to ER stress, prior to apoptosis.