Autophagy is a highly conserved degradation process by which intracellular components, including soluble macromolecules (e.g. nucleic acids, proteins, carbohydrates, and lipids) and dysfunctional organelles (e.g. mitochondria, ribosomes, peroxisomes, and endoplasmic reticulum) are degraded by the lysosome. Autophagy is orchestrated by the autophagy related protein (Atg) composed protein complexes to form autophagosomes, which fuse with lysosomes to generate autolysosomes where the contents are degraded to provide energy for cell survival in response to environmental and cellular stress. Autophagy is an important player in cardiovascular disease development such as atherosclerosis, cardiac ischemia/reperfusion, cardiomyopathy, heart failure and hypertension. Autophagy in particular contributes to cardiac ischemia, hypertension and diabetes by interaction with reactive oxygen species generated in endoplasmic reticulum and mitochondria. This review highlights the dual role of autophagy in cardiovascular disease development. Full recognition of autophagy as an adaptive or maladaptive response would provide potential new strategies for cardiovascular disease prevention and management.

Nitroxyl (HNO) exerts inotropic and lusitropic effects in myocardium, in part via activation of SERCA (sarcoplasmic reticulum calcium ATPase). To elucidate the molecular mechanism, adult rat ventricular myocytes were exposed to HNO derived from Angeli's salt. HNO increased the maximal rate of thapsigargin-sensitive Ca 2؉ uptake mediated by SERCA in sarcoplasmic vesicles and caused reversible oxidative modification of SERCA thiols. HNO increased the S-glutathiolation of SERCA, and adenoviral overexpression of glutaredoxin-1 prevented both the HNO-stimulated oxidative modification of SERCA and its activation, as did overexpression of a mutated SERCA in which cysteine 674 was replaced with serine. Thus, HNO increases the maximal activation of SERCA via S-glutathiolation at cysteine 674. N itroxyl (HNO), the 1-electron reduced and protonated form of nitric oxide (NO), exerts a bioactivity profile that differs markedly from NO 1,2 and other reactive nitrogen species such as peroxynitrite. 3 In the cardiovascular system, HNO derived from Angeli's salt (AS) exerts inotropic and lusitropic effects in the myocardium 4 and causes relaxation of vascular smooth muscle. 5,6 These observations have raised the possibility that HNO is involved in cardiovascular regulation and/or may have therapeutic potential.In cardiac myocytes, HNO increases calcium cycling in association with increasing the activities of SERCA (sarcoplasmic reticulum ATPase) and the calcium release channel (CRC). 1 In vascular smooth muscle cells SERCA activity can be increased by NO-induced S-glutathiolation. 7 Accordingly, we hypothesized that in cardiac myocytes HNO can activate SERCA via S-glutathiolation. Materials and MethodsIn all experiments, adult rat ventricular myocytes (ARVMs) 8 were exposed for 15 minutes to 500 mol/L AS dissolved in 10 mmol/L NaOH. Detailed methods are provided in the online supplement at http://circres.ahajournals.org. Results and Discussion HNO Activation of SERCA Involves Reversible, Oxidative Thiol ModificationAS increased myocyte shortening (Ϸ2-fold) and accelerated relaxation ( Figure I in the online data supplement), confirming the findings of Tocchetti et al. 1 In the absence of dithiothreitol (DTT), AS (500 mol/L; 15 minutes) increased maximal SERCA activity Ϸ3-fold ( Figure 1A). In the pres-

Rationale: Vascular smooth muscle cell (SMC) migration is an important pathological process in several vascular occlusive diseases, including atherosclerosis and restenosis, both of which are accelerated by diabetes mellitus.Objective: To determine the mechanisms of abnormal vascular SMC migration in type 2 diabetes, the obese Zucker rat (ZO), a model of obesity and insulin resistance, was studied. Key Words: nitric oxide Ⅲ cell migration Ⅲ NADPH oxidase Ⅲ obese Zucker rat Ⅲ TGF-␤1 Ⅲ Smad2 D iabetic patients have a much higher morbidity and mortality from cardiovascular diseases, including atherosclerosis and restenosis, compared with other patients. Vascular smooth muscle cell (SMC) migration contributes significantly to these pathological processes. Generally, SMCs remain quiescent in the vasculature, but when the endothelial layer is disrupted, the underlying SMCs migrate from media to intima and form the neointima. This process is accelerated by diabetes mellitus. Numerous clinical studies have indicated that diabetic patients have a higher incidence of restenosis after percutaneous coronary interventions compared with patients without diabetes. [1][2][3] Nitric oxide (NO), the biologically active component of endothelium-derived relaxing factor, has critical roles in the maintenance of vascular homeostasis. The sarco-/ endoplasmic reticulum Ca 2ϩ ATPase (SERCA) plays a very important role in maintaining intracellular calcium levels by taking up calcium into sarco-/endoplasmic reticulum. Previous studies showed that NO decreases intracellular calcium, which causes SMC relaxation and inhibits growth and migration. Our previous studies showed that NO upregulates SERCA activity by S-glutathiolation of the most reactive thiol on cysteine-674 (C674) and thereby inhibits SMC migration. 4 Impaired NO-induced relaxation of atherosclerotic arteries or inhibition of migration of cultured SMCs exposed to high glucose was attributable to irreversible oxidation of SERCA C674, which prevents the S-glutathiolation and increase in SERCA activity required for the response to NO. 5 A recent report that vascular injury, which is normally inhibited by NO, is unaffected in Original Methods and Results: