Viewing a stressful episode of ER: is ATF6 the triage nurse?

How cardiac cells sense, respond, and adapt to acute and chronic changes of their metabolic and environmental milieu remain among the most enigmatic and fundamental questions in contemporary cardiovascular biology and medicine. With more than 700 000 deaths and 6 million hospital discharges annually in the U.S., ischemic heart disease remains a major public health problem. If prompt therapy is delayed, myocardial injury from depletion of high-energy phosphates from inhibition of oxidative phosphorylation is inevitable. Ischemia/reperfusion (I/R) also unleashes a cascade of cellular and molecular events whose sequalae may sustain organ function at diminished capacity but, beyond a critical balance, threatens the organism’s survival. Reactive oxygen and nitrogen species (ROS; RNS), released from the mitochondria and other sources, alter the tertiary and quaternary structures of proteins, exposing their hydrophobic residues to allow conformational tendencies toward protein misfolding and aggregation.1 Nevertheless, highly sophisticated schemes equipped with molecular sensors, rapid response pathways, and adaptor mechanisms have evolved to mitigate the accumulation of unfolded proteins in a compartment specific manner, principally the cytoplasm and endoplasmic reticulum (ER). Although the cardiovascular field has paid considerably more attention to the cytoprotective mechanisms of heat shock proteins in response to I/R, termed the “classical” heat shock response, a parallel series of events has been unfolding at a breathtaking pace in the ER, with arguably considerable excitement to warrant a sneak preview of the article published in this issue of Circulation Research. To place into perspective the current buzz being garnered by the ER requires a brief discussion of more familiar themes in the field, which were developed thanks to the pioneering efforts of cardiovascular scientists, and others, working on the complementary stress response network, best exemplified by heat shock “stress” proteins and their transcriptional regulators. First discovered by Ritossa in Drosophila, the capacity for cells to augment synthesis of distinct classes of heat shock proteins (HSPs) in response to heat and other stressors (eg, hypoxia and ischemia/reperfusion), termed the heat shock response, has emerged as a paradigm for inducible gene expression.2 Reminiscent of ischemia preconditioning (IPC) in which prior sublethal ischemia confers transient protection to a subsequent prolonged bout of ischemia, increased synthesis of HSPs by different maneuvers was similarly shown to produce cross-tolerance for ischemic cardioprotection. Whereas most HSPs are constitutively expressed in unstressed cells, stress-inducible HSP expression is controlled at the transcriptional level by heat shock transcription factor 1 (HSF1) by mechanisms involving unfolded proteins and redox-dependent stress signals. Transgenic overexpression of Hsp25, Hsp70i, and B-crystallin can individually confer ischemic cardioprotection in vivo, possibly through their roles as molecular chaperones and antiapoptotic agents, legitimizing their therapeutic potential in the armamentarium for ischemic cardioprotection.3,4 While the aforementioned Hsps are localized in the cytosol and nucleus, the recent intriguing elucidation of the complementary transcriptional networks that govern ER-resident chaperones has heightened interest in their direct relevance to cardiac biology and (patho)physiology (Figure). It is generally not widely appreciated that the ER contains the highest concentration of intracellular Ca , an essential requirement used by Ca -ATPases for intraluminal calcium transport. In contrast to the reducing environment of the cytoplasm, the ER requires an oxidizing state to facilitate disulfide bonding formation during maturation along the protein folding pathway of secretory and membrane-bound proteins, a process termed oxidative protein folding.5,6 However, most secretory and noncytosolic nascent proteins with exposed hydrophobic residues will readily aggregate if not prevented by the enzymatic activities (eg, peptidyl prolyl isomerase) and specialized properties of molecular chaperones. Accumulation of misfolded proteins, beyond some critical threshold, is sensed in the ER and activates the evolutionarily conserved unfolded stress response (UPR), also termed the ER stress response.7 This response is mediated by at least three regulatory pathways, two involved in transcription regulation (ATF6, XBP-1) and the third controlling protein translation (eIF2 , kinase). First identified in a yeast one-hybrid screen, ATF6 is a basic leucine zipper (bZIP) protein that binds to the consensus ER stress response element (ERSE) and enhances transcription of genes encoding glucose regulated proteins (Grp) Grp78, Grp94, and calreticulum (Figure).7 In response to ER stress, endogenous ATF6 is a 90-kDA protein of 670 amino acids, which translocates from the ER to the Golgi coincident with proteolytic cleavage to the transcriptionally competent 50kDA protein by a process termed regulated intramembrane The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Center for Cardiovascular Translational Biomedicine, Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City. Correspondence to Ivor J. Benjamin MD, FAHA, Center for Cardiovascular Translational Biomedicine, Division of Cardiology, University of Utah Health Sciences Center, 30 North 1900 East, Salt Lake City, UT 84132. E-mail [email protected] (Circ Res. 2006;98:1120-1122.) © 2006 American Heart Association, Inc.