Discovery of mesencephalic astrocyte-derived neurotrophic factor (MANF) as a secreted, endoplasmic reticulum stress response-induced gene, and its role in the heart

Activation of the endoplasmic reticulum stress response (ERSR) occurs when nascent protein folding in the ER is impeded. Such impediment can occur in the heart upon myocardial ischemia, when there is a lack of oxygen and nutrient flow to the heart, leading to ischemic damage. This can be minimized by activation of protective pathways such as the ERSR, in particular, the ATF6 branch of the ERSR. ATF6, a transcription factor, induced numerous genes in the heart, including mesencephalic astrocyte-derived neurotrophic factor (MANF). MANF is induced in cardiomyocytes, in the heart, in response to in vivo myocardial infarction and in response to simulated ischemia, in neonatal rat ventricular cardiac myocyte cultures, in vitro.;Unlike many other ER-resident ERSR induced proteins, MANF has a non-canonical ER-retention sequence, which may result in its conditional secretion. MANF expression in resulted in protection from serum starvation-induced apoptosis. MANF knockdown in cardiomyocytes resulted in increased susceptibility to simulated ischemia/reperfusion (sI/R)-induced cell death, while addition of recombinant MANF (rMANF) conferred protection, suggesting a possible autocrine/paracrine function. MANF overexpression led to decreased cardiomyocyte growth, while MANF knockdown exacerbated hypertrophy, as characterized by activation of the MAPK pathway, and NFAT, and induction of hypertrophic growth markers such as ANF. rMANF had no effect on cardiomyocyte growth, suggesting a role for intracellular MANF.;While the exact mechanism of action is still unclear, MANF overexpression during sI/R enhanced activation of pro-survival signaling pathways, such as the MAPK and PI3K/Akt, and addition of rMANF also activated the MAPK pathway.;These findings indicate that MANF may have multiple mechanisms of action, and that it may be dependent on its location (intracellular or extracellular) and the nature of the stress (pro-growth vs ER stress). While further studies are required to fully understand the role of MANF, these studies, for the first time, demonstrate that MANF not only protects myocytes from ER stress-induced cell death, but also from hypertrophic growth, which is known to lead to myocyte death, and eventually heart failure.