title: Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases.
abstract: Various cellular perturbations implicated in the pathophysiology of human diseases, including cardiovascular and neurodegenerative diseases, diabetes mellitus, obesity, and liver diseases, can alter endoplasmic reticulum (ER) function and lead to the abnormal accumulation of misfolded proteins. This situation configures the so-called ER stress, a form of intracellular stress that occurs whenever the protein-folding capacity of the ER is overwhelmed. Reduction in blood flow as a result of atherosclerotic coronary artery disease causes tissue hypoxia, a condition that induces protein misfolding and ER stress. In addition, ER stress has an important role in cardiac hypertrophy mainly in the transition to heart failure (HF). ER transmembrane sensors detect the accumulation of unfolded proteins and activate transcriptional and translational pathways that deal with unfolded and misfolded proteins, known as the unfolded protein response (UPR). Once the UPR fails to control the level of unfolded and misfolded proteins in the ER, ER-initiated apoptotic signaling is induced. Furthermore, there is considerable evidence that implicates the presence of oxidative stress and subsequent related cellular damage as an initial cause of injury to the myocardium after ischemia/reperfusion (I/R) and in cardiac hypertrophy secondary to pressure overload. Oxidative stress is counterbalanced by complex antioxidant defense systems regulated by a series of multiple pathways, including the UPR, to ensure that the response to oxidants is adequate. Nuclear factor-E2-related factor (Nrf2) is an emerging regulator of cellular resistance to oxidants; Nrf2 is strictly interrelated with the UPR sensor called pancreatic endoplasmic reticulum kinase. A series of studies has shown that interventions against ER stress and Nrf2 activation reduce myocardial infarct size and cardiac hypertrophy in the transition to HF in animals exposed to I/R injury and pressure overload, respectively. Finally, recent data showed that Nrf2/antioxidant-response element pathway activation may be of importance also in ischemic preconditioning, a phenomenon in which the heart is subjected to one or more episodes of nonlethal myocardial I/R before the sustained coronary artery occlusion.
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy. Electronic address: Luciano.cominacini@univr.it.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cominacini
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mozzini
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Ulisse
authors.initials: U
authors.lastname: Garbin
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pasini
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Stranieri
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Solani
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vallerio
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Irene Alessandra
authors.initials: IA
authors.lastname: Tinelli
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fratta Pasini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051267:NF-E2-Related Factor 2
keywords: Coronary artery disease; Endoplasmic reticulum stress; Free radicals; Heart failure; Left-ventricular hypertrophy; Nrf2