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mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes

The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of protein synthesis that senses and responds to a variety of stimuli to coordinate cellular metabolism with environmental conditions. To ensure that protein synthesis is …

IRE1/XBP1 and Endoplasmic Reticulum Signaling--From Basic to Translational Research for Cardiovascular Disease

VARS2 depletion leads to activation of the integrated stress response and disruptions in mitochondrial fatty acid oxidation

Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological cell growth of cardiomyocytes

RNA-binding proteins (RBPs) control critical aspects of cardiomyocyte function, but the repertoire of active RBPs in cardiomyocytes during the growth response is largely unknown. We define RBPs in healthy and diseased cardiomyocytes at a system-wide …

Muscle-specific Cand2 is translationally upregulated by mTORC1 and promotes adverse cardiac remodeling

A multi-network comparative analysis of transcriptome and translatome identifies novel hub genes in cardiac remodeling

Our understanding of the transition from physiological to pathological cardiac hypertrophy remains elusive and largely based on reductionist hypotheses. Here, we profiled the translatomes of 15 mouse hearts to provide a molecular blueprint of altered …

ER stress-induced secretion of proteins and their extracellular functions in the heart

Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and …

Proteomic analysis of the cardiac myocyte secretome reveals extracellular protective functions for the ER stress response

The effects of ER stress on protein secretion by cardiac myocytes are not well understood. In this study, the ER stressor thapsigargin (TG), which depletes ER calcium, induced death of cultured neonatal rat ventricular myocytes (NRVMs) in high media …

Mesencephalic astrocyte-derived neurotrophic factor is an ER-resident chaperone that protects against reductive stress in the heart

We have previously demonstrated that ischemia/reperfusion (I/R) impairs endoplasmic reticulum (ER)-based protein folding in the heart and thereby activates an unfolded protein response sensor and effector, activated transcription factor 6$α$ (ATF6). …

Saraf-dependent activation of mTORC1 regulates cardiac growth

Pathological cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signaling pathways regulating intracellular Ca2+ homeostasis that control adaptive and pathological cardiac growth may enable identification …