Repression of miR‐142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy

Abstract

An increase in cardiac workload, ultimately resulting in hypertrophy, generates oxidative stress and therefore requires the activation of both survival and growth signal pathways. Here, we wanted to characterize the regulators, targets and mechanistic roles of miR-142, a microRNA (miRNA) negatively regulated during hypertrophy. We show that both miRNA-142-3p and -5p are repressed by serum-derived growth factors in cultured cardiac myocytes, in models of cardiac hypertrophy in vivo and in human cardiomyopathic hearts. Levels of miR-142 are inversely related to levels of acetyltransferase p300 and MAPK activity. When present, miR-142 inhibits both survival and growth pathways by directly targeting nodal regulators p300 and gp130. MiR-142 also potently represses multiple components of the NF-κB pathway, preventing cytokine-mediated NO production and blocks translation of α-actinin. Forced expression of miR-142 during hypertrophic growth induced extensive apoptosis and cardiac dysfunction; conversely, loss of miR-142 fully rescued cardiac function in a murine heart failure model. Downregulation of miR-142 is required to enable cytokine-mediated survival signalling during cardiac growth in response to haemodynamic stress and is a critical element of adaptive hypertrophy.

Extracellular vesicles in lung microenvironment and pathogenesis

“…EVs derived from pathogen-infected mammalian cells have a variety of proinflammatory functions that increase the efficacy of innate immunity. It has been recently reported that acute stressor exposure, such as to heat and oxidative stress, also modifies EV miRNAs associated with the TLR-mediated inflammatory response [36][37][38]. Importantly, these variations of EV components result from targeted selection, not random incorporation into the MVB [32,39].…”

MicroRNA-142 Inhibits Proliferation and Promotes Apoptosis in Airway Smooth Muscle Cells During Airway Remodeling in Asthmatic Rats via the Inhibition of TGF-β -Dependent EGFR Signaling Pathway

“…miR-142 is a global inhibitor of cytokine signaling. Preventing the physiological downregulation of miR-142 has been shown to induce apoptosis and deplete cytokine-mediated survival signals [9]. The transforming growth factor-β (TGF-β) family includes several TGF-β isoforms (e.g., TGF-β1, TGF-β2, and TGF-β3) in addition to inhibins, activins, differentiation factors and growth factors; the diverse roles of TGF-β family members include regulation of immune responses, chemotaxis for inflammatory cells, and proliferation inhibition of many cell types [2].…”

MiR-142-5p and miR-486-5p as biomarkers for early detection of chronic antibody-mediated rejection in kidney transplantation

“…The expression of miR-142-5p has been proposed to be associated with extensive apoptosis and cardiac dysfunction in a murine heart failure model (Sharma, Liu et al, 2012). The difference between our study and Danger´s results was that stable patients group with DSA (group II-2a) were included.…”