Physical activity pacifies the problematic p66Shc

The impaired capacity of vasculature to adjust to changes in blood flow is a contributing factor in myocardial ischemia, infarction and subsequent dysfunction. With age and other co-morbid conditions, the ability of vascular beds to control vessel lumen diameters decline. Pharmacological tools are generally used to rectify the disparity between the demand and supply of oxygenated blood. Other than the available pharmacological tools, exercise is a proven way to improve cardiovascular function in patients as well as in healthy individuals. There is evidence that exercise increases coronary blood flow. However, the mechanism involved in these irrefutable benefits of exercise is poorly understood. Studies suggest that physical activity controls physiological functions via endocrine and paracrine regulators. There is evidence that exercise also affects the epigenetic modifications via which transcriptional processes are regulated. These epigenetic markers are of high pathophysiological significance as these modifications persist longer and are also transmitted to the next generation. Physical activity and the induced stretch of isolated muscle fibers are reported to control epigenetic modifications (e.g. methylation) at the promoters of many genes involved in metabolic processes independent of circulatory or paracrine factors. These findings suggest that exercise can erase epigenetic markers and highlights the significance of physical activity in controlling health and disease states via epigenetic modifications. The clinical evaluation of vascular endothelial function, especially in the microvascular bed, has been very challenging. Microvessels present in the retina have been extensively studied for their suitability to reflect the overall status of vascular function. Recent studies have identified a correlation between retinal vessel diameter and various cardiovascular diseases. Importantly, the change in retinal vessel diameter is responsive to physical activity. In this issue, Streese et al. show that physical activity is associated with improved retinal microvascular phenotype, reduced systemic oxidative stress and decreased methylation of the p66Shc promoter region. Human subjects were divided into three groups based on activity level and the presence or absence of cardiovascular risk factors. Lack of physical activity was associated with narrower arterioles in healthy individuals independent of age, sex and medications. In addition, the arteriolarto-venular-diameter ratio (AVR) was lower in the sedentary individuals with cardiovascular risk factors compared to those without. These findings complement an earlier report showing that high intensity interval training increases the retinal arteriolar diameter. Physical activity is also known to regulate circulating cells. It increases the number of endothelial progenitor cells and improves their function in patients with chronic heart failure. In the study by Streese et al., the authors show that the level of physical activity is associated with the transcriptional control of redox protein p66Shc (the 66kD isoform of Shc adaptor proteins) in circulating peripheral blood mononuclear cells (PBMCs). Although p66Shc has been well studied for its role in vascular pathologies, clinical investigations are still scarce. Associations between increased levels of p66Shc mRNA in patients with coronary artery diseases, diabetes and its correlation with the onset of new diabetic complications over time have been reported. Streese et al. show that hypomethylation in CpG islands in the promoter region of p66Shc is directly correlated with a lack of physical activity. This is in tune with their earlier report showing that increasing physical activity can reduce the transcription of p66Shc by controlling promoter methylation. Also, the lower level of p66Shc transcript in PBMCs was associated with reduced oxidative stress. The novel findings of this study will fuel more studies to examine the different aspects of the relationship between p66Shc and physical activity. Generation of