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.
Highlights
Postnatal growth of the heart, as during childhood and athletic training, requires an increase in myocyte size, or hypertrophy (Grossman, 1980; Moore et al, 1980)
MiR-142-5p and -3p are downregulated during cardiac hypertrophy In both p300 transgenic (p300tg) and wild-type mice, miR-142-5p and -3p levels were very low in the period of adaptive cardiac growth between birth and adulthood at 2 months, relative to levels achieved after 3 months (Fig 1A and B)
Downregulation of miR-142 during cardiac growth is critical to cell survival and cardiac performance In this study, we demonstrate an inverse relationship between levels of miR-142 and cardiac hypertrophy in multiple physiologic and pathologic settings
Summary
Postnatal growth of the heart, as during childhood and athletic training, requires an increase in myocyte size, or hypertrophy (Grossman, 1980; Moore et al, 1980). Diseases such as hypertension and aortic valvular stenosis that increase cardiac workload induce cardiac myocyte hypertrophy, often accompanied by alterations in the shape and structure of the heart and by varying degrees of fibrosis, attenuation of blood supply, metabolic alterations, changes in calcium handling and the activation of harmful signal transduction path-. The elucidation of downstream effectors of p300 could provide insight into mechanisms of adaptive versus maladaptive cardiac growth
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