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There were errors published in J. Cell Sci. 124, 2143Sci. 124, -2152 In the section given below, PtdIns(3,4,5)P 3 was on four occasions incorrectly printed instead of the correct Ins(1,4,5)P 3 .We apologise for this mistake. Increased mitochondrial Ca2+ drives the adaptive metabolic boost observed during early phases of ER stress Increases in mitochondrial respiration and ATP production are often consequences of increases in mitochondrial Ca 2+ (Green and Wang, 2010). In order to determine whether early phases of ER stress induced by tunicamycin increased mitochondrial Ca 2+ , we treated cells expressing cytosolic or mitochondrial aequorins with histamine [which evokes Ins(1,4,5)P 3 -dependent Ca2+ release] and compared their mitochondrial Ca 2+ uptake. We observed that histamine led to a mitochondrial Ca 2+ uptake that was significantly higher in tunicamycinpretreated cells (P<0.05; 4 hours) than in untreated cells (Fig. 6A). Cytosolic Ca 2+ increased similarly in tunicamycin-treated and untreated cells (Fig. 6B). These results indicate that the differences in mitochondrial Ca 2+ levels are not due to altered Ca 2+ release mediated by the Ins(1,4,5)P 3 receptor but to an enhanced mitochondrial Ca 2+ uptake, presumably due to the increased apposition of ER and mitochondrial Ca 2+ channels. By using a different dye, Fura-2, we monitored the peak cytosolic Ca 2+ levels after thapsigargin addition, reflecting the kinetics of Ca 2+ release after sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) inhibition. After 4 hours of tunicamycin treatment, the thapsigargin-induced Ca 2+ peak was increased, and it was further elevated by inhibition of mitochondrial Ca 2+ uptake using Ru360 (Fig. 6C). These results suggest that, besides the Ins(1,4,5)P 3 -receptor-mediated direct Ca 2+ transfer from the ER to neighboring mitochondria, an additional phenomenon associated with the early phases of ER stress involves Ca 2+ leak from the ER, also resulting in mitochondrial Ca 2+ uptake. Indeed, no mitochondrial Ca 2+ uptake following the thapsigargin-induced Ca 2+ leak was observed in Mfn2-knockout cells (Fig. 6D), which is reflected by the lack of effect of Ru360. This result further indicates that juxtaposition of mitochondria with the ER is necessary for the mitochondrial Ca 2+ uptake evoked by Ca 2+ leak during early phases of ER stress.Finally, to test whether mitochondrial Ca 2+ levels control the metabolic mitochondrial boost, we measured oxygen consumption rates resulting from OXPHOS in the presence of the Ins(1,4,5)P 3 receptor inhibitor xestospongin B or the mitochondrial Ca 2+ uptake inhibitor RuRed. We observed that both xestospongin B and RuRed decreased the rate of oxygen consumption after tunicamycin treatment (Fig. 7A,B), which confirms that increased mitochondrial Ca 2+ uptake, resulting from ER-mitochondrial coupling, is necessary for the metabolic response observed during early phases of ER stress. Therefore, in order to evaluate whether the early metabolic boost forms part of an adaptive response triggere...

| The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and IIinitially thought to be biologically inactive -have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7 , angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT 2 R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical reninangiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review , we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Although treatments have improved, development of novel therapies for patients with CVD remains a major research goal. Apoptosis, necrosis, and autophagy occur in cardiac myocytes, and both gradual and acute cell death are hallmarks of cardiac pathology, including heart failure, myocardial infarction, and ischemia/reperfusion. Pharmacological and genetic inhibition of autophagy, apoptosis, or necrosis diminishes infarct size and improves cardiac function in these disorders. Here, we review recent progress in the fields of autophagy, apoptosis, and necrosis. In addition, we highlight the involvement of these mechanisms in cardiac pathology and discuss potential translational implications.

Insulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFκB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFκB pathway.

Autophagy in the vascular systemEndothelial cells. Autophagy can be regulated in vascular endothelial cells by compounds circulating in the bloodstream or localized within the subendothelial layer of atherosclerotic plaque. For example, in cultured HUVECs, vitamin D increases beclin 1, a key comCardiovascular disease is the leading cause of death worldwide. As such, there is great interest in identifying novel mechanisms that govern the cardiovascular response to disease-related stress. First described in failing hearts, autophagy within the cardiovascular system has been widely characterized in cardiomyocytes, cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, and macrophages. In all cases, a window of optimal autophagic activity appears to be critical to the maintenance of cardiovascular homeostasis and function; excessive or insufficient levels of autophagic flux can each contribute to heart disease pathogenesis. In this Review, we discuss the potential for targeting autophagy therapeutically and our vision for where this exciting biology may lead in the future.

Autophagy is a catabolic recycling pathway triggered by various intra- or extracellular stimuli that is conserved from yeast to mammals. During autophagy diverse cytosolic constituents are enveloped by double-membrane vesicles, autophagosomes, which later fuse with lysosomes or the vacuole in order to degrade their cargo. Dysregulation in autophagy is associated with a diverse range of pathologies including cardiovascular disease, the leading cause of death in the world. As such, there is great interest in identifying novel mechanisms that govern the cardiovascular response to disease-related stress. First described in failing hearts, autophagy within the cardiovascular system has been widely characterized in cardiomyocytes, cardiac fibroblasts, endothelial cells and vascular smooth muscle cells. In all cases, a window of optimal autophagic activity appears to be critical to the maintenance of cardiovascular homeostasis and function; excessive or insufficient levels of autophagic flux can each contribute to heart disease pathogenesis. Here we review the molecular mechanisms that govern autophagosome formation and analyze the link between autophagy and cardiovascular disease.