Cardiac hypertrophy (CH) is an adaptive response of the heart to pressure overload. It is a common pathological feature in the natural course of some major cardiovascular diseases, like, hypertension and myocardial infarction. Cardiac hypertrophy is strongly associated with an increased risk of heart failure and sudden cardiac death. The complex and dynamic pathophysiological mechanisms of CH has been the focus of intense scientific investigation, in an effort to design preventive and curative strategies. Oxidative stress has been identified as one of the key contributing factors in the development of cardiac hypertrophy. In this review, evidences supporting the oxidative stress as a cause of cardiac hypertrophy with emphasis on mitochondrial oxidative stress and possible options for pharmacological interventions have been discussed. Reactive oxygen species (ROS) also activate a broad variety of hypertrophy signaling kinases and transcription factors, like, MAP kinase, NF K-B, etc. In addition to profound alteration of cellular function, ROS modulate the extracellular matrix function, evidenced by increased interstitial and perivascular fibrosis. Translocator protein (TSPO) present in the outer mitochondrial membrane is known to be involved in oxidative stress and cardiovascular pathology. Recently, its role in cardiac hypertrophy has been reported by us. All these evidences strongly provide support to beneficial role of drugs which selectively interfere with the generation of free radicals or augment endogenous antioxidants in cardiac hypertrophy.

It may be concluded that on chronic administration, CL suppresses inflammation and brings clinical improvement in patients of KOA, which may be observed by decreased level of IL-1β and VAS/WOMAC scores, respectively. At the same time, CL decreases the oxidative stress also.

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The 66-kDa Src homology 2 domain-containing protein (p66Shc) is a master regulator of reactive oxygen species (ROS). It is expressed in many tissues where it contributes to organ dysfunction by promoting oxidative stress. In the vasculature, p66Shc-induced ROS engenders endothelial dysfunction. Here we show that p66Shc is a direct target of the Sirtuin1 lysine deacetylase (Sirt1), and Sirt1-regulated acetylation of p66Shc governs its capacity to induce ROS. Using diabetes as an oxidative stimulus, we demonstrate that p66Shc is acetylated under high glucose conditions and is deacetylated by Sirt1 on lysine 81. High glucose-stimulated lysine acetylation of p66Shc facilitates its phosphorylation on serine 36 and translocation to the mitochondria, where it promotes hydrogen peroxide production. Endothelium-specific transgenic and global knockin mice expressing p66Shc that is not acetylatable on lysine 81 are protected from diabetic oxidative stress and vascular endothelial dysfunction. These findings show that p66Shc is a target of Sirt1, uncover a unique Sirt1-regulated lysine acetylationdependent mechanism that governs the oxidative function of p66Shc, and demonstrate the importance of p66Shc lysine acetylation in vascular oxidative stress and diabetic vascular pathophysiology.p66Shc | sirt1 | lysine acetylation | diabetes | oxidative stress

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