Abstract-Growing evidence indicates that chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is integral in the development of cardiovascular diseases (CVD). These ROS can be released from nicotinamide adenine dinucleotide (phosphate) oxidase, xanthine oxidase, lipoxygenase, mitochondria, or the uncoupling of nitric oxide synthase in vascular cells. ROS mediate various signaling pathways that underlie vascular inflammation in atherogenesis: from the initiation of fatty streak development through lesion progress to ultimate plaque rupture. Various animal models of oxidative stress support the notion that ROS have a causal role in atherosclerosis and other cardiovascular diseases. Human investigations also support the oxidative stress hypothesis of atherosclerosis. Oxidative stress is the unifying mechanism for many CVD risk factors, which additionally supports its central role in CVD. Despite the demonstrated role of antioxidants in cellular and animal studies, the ineffectiveness of antioxidants in reducing cardiovascular death and morbidity in clinical trials has led many investigators to question the importance of oxidative stress in human atherosclerosis. Others have argued that the prime factor for the mixed outcomes from using antioxidants to prevent CVD may be the lack of specific and sensitive biomarkers by which to assess the oxidative stress phenotypes underlying CVD. A better understanding of the complexity of cellular redox reactions, development of a new class of antioxidants targeted to specific subcellular locales, and the phenotype-genotype linkage analysis for oxidative stress will likely be avenues for future research in this area as we move toward the broader use of pharmacological and regenerative therapies in the treatment and prevention of CVD.

Abstract-Increased production of reactive oxygen species in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are associated with atherosclerosis or cardiomyopathy in human investigations and animal models of oxidative stress. Moreover, major precursors of atherosclerosis-hypercholesterolemia, hyperglycemia, hypertriglyceridemia, and even the process of aging-all induce mitochondrial dysfunction.

contributed equally to this work Induction of molecular chaperones is the characteristic protective response to environmental stress, and is regulated by a transcriptional program that depends on heat shock factor 1 (HSF1), which is normally under negative regulatory control by molecular chaperones Hsp70 and Hsp90. In metazoan species, the chaperone system also provides protection against apoptosis. We demonstrate that the dual function cochaperone/ubiquitin ligase CHIP (C-terminus of Hsp70-interacting protein) regulates activation of the stress-chaperone response through induced trimerization and transcriptional activation of HSF1, and is required for protection against stress-induced apoptosis in murine ®broblasts. The consequences of this function are demonstrated by the phenotype of mice lacking CHIP, which develop normally but are temperature-sensitive and develop apoptosis in multiple organs after environmental challenge. CHIP exerts a central and unique role in tuning the response to stress at multiple levels by regulation of protein quality control and transcriptional activation of stress response signaling.

Aims: Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe -/ -mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD. Results: Both aged (16 months) Apoe -/ -and Apoe -/ -/p47phox -/ -mice had increased atherosclerotic lesion area, aortic stiffness, and systolic dysfunction compared with young (4 months) cohorts. Cellular and mitochondrial ROS (mtROS) levels were significantly higher in aortic wall and vascular smooth muscle cells (VSMCs) from aged wild-type and p47phox -/ -mice. VSMCs from aged mice had increased mitochondrial protein oxidation and dysfunction and increased vascular cell adhesion molecule 1 expression, which was abrogated with (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) treatment. NOX4 expression was increased in the vasculature and mitochondria of aged mice and its suppression with shRNA in VSMCs from aged mice decreased mtROS levels and improved function. Increased mtROS levels were associated with enhanced mitochondrial NOX4 expression in aortic VSMCs from aged subjects, and NOX4 expression levels in arterial wall correlated with age and atherosclerotic severity. Aged Apoe -/ -mice treated with MitoTEMPO and 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo [4,3-c]pyridine-3,6(2H,5H)-dione had decreased vascular ROS levels and atherosclerosis and preserved vascular and cardiac function. Innovation and Conclusion: These data suggest that NOX4, but not NOX1/2, and mitochondrial oxidative stress are mediators of CVD in aging under hyperlipidemic conditions. Regulating NOX4 activity/expression and using mitochondrial antioxidants are potential approaches to reducing aging-associated CVD.

Abstract-Reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) activate intracellular signal transduction pathways implicated in the pathogenesis of cardiovascular disease. H 2 O 2 is a mitogen for rat vascular smooth muscle cells (VSMCs), and protein tyrosine phosphorylation is a critical event in VSMC mitogenesis. Therefore, we investigated whether the mitogenic effects of H 2 O 2 , such as stimulation of extracellular signal-regulated kinase (ERK)2, are mediated via activation of cytoplasmic Janus tyrosine kinases (JAKs). JAK2 was activated rapidly in VSMCs treated with H 2 O 2 , and signal transducers and activators of transcription (STAT) STAT1 and STAT3 were tyrosine-phosphorylated and translocated to the nucleus in a JAK2-dependent manner. A ccumulating evidence supports a critical role for oxidative stress in the pathogenesis of atherosclerosis, cancer, and other human diseases. 1 High levels of reactive oxygen species (ROS) damage DNA and inactivate proteins, 2 resulting in chronic cellular dysfunction. Many cell types have also harnessed ROS, albeit in lower concentrations, as intracellular signaling molecules to mediate growth factor and cytokine responses. 3,4 Modulation of growth responses by ROS has been demonstrated in a number of cell types, including vascular smooth muscle cells (VSMCs). 5,6 Stimulation of VSMC proliferation by ROS is thought to be a critical step in atherosclerotic lesion formation. 7 Tyrosine phosphorylation of cellular proteins and the consequent induction of transcription of early-response genes are key determinants of cell growth and differentiation in response to mitogenic signaling. 8 VSMC mitogens such as platelet-derived growth factor and epidermal growth factor activate receptor protein tyrosine kinases on binding, which stimulate intracellular signaling pathways that result in mitogen-activated protein kinase activation. 9,10 Other mitogens, such as thrombin and angiotensin II, activate G proteincoupled receptors that do not possess intrinsic tyrosine kinase activity but require tyrosine phosphorylation events to induce mitogenesis. [11][12][13] The necessary role for protein tyrosine phosphorylation in mitogenesis elicited by thrombin and ROS indicates that these mitogens may utilize cytoplasmic protein tyrosine kinases in their signaling cascade. Forming 1 such group of tyrosine kinases are Janus kinases (JAKs), which along with their substrates, signal transducers and activators of transcription (STATs), have hitherto been characterized as essential mediators of cytokine and polypeptide hormone-induced signaling. 8,14 Members of the JAK/STAT pathway mediate at least some biological effects of angiotensin II, 15 plateletderived growth factor-BB, 15,16 and endothelial growth factor. 17 Activation of the JAK/STAT pathway has also been observed in response to generation of intracellular ROS 18 and exogenous hydrogen peroxide (H 2 O 2 ). 19 On phosphorylation by JAKs of tyrosine residues, activated STAT dimers translocate to the nucleus to transactivate tar...