Ebook Resveratrol protects against insulin resistance and improves left ventricular contractile function by activating estrogen receptor
Heart disease is a leading cause of death in diabetic patients; with coronary artery disease (CAD) and atherosclerosis being the primary reasons for increased incidence of cardiovascular dysfunction. However, a predisposition to heart failure might also reflect the effects of underlying abnormalities in cardiac diastolic function that can be detected in asymptomatic patients with diabetes. Several etiological factors have been put forward to explain why hyperglycemia and/or diabetes tend to lead to diabetic cardiomyopathy. The accumulation of connective tissues, insoluble collagens, and abnormalities of various proteins that regulate ion flux (specifically intracellular calcium), has been proposedas an explanation for left ventricular wall stiffness and contractile dysfunctions. Recently, the idea that diabetic cardiomyopathy could also occur as a consequence of metabolic alterations.
It is well known that under normal conditions, the adult heart utilizes predominantly long chain fatty acids for most of its energy requirements (60–90%); with glucose and lactate providing the rest. Since Randle et al. proposed the existence of a glucose–fatty acid cycle in 1963, the link between glucose and fatty acid metabolism has been widely accepted. Disruption of the balance between glucose and fatty acid metabolism is often a primary defect observed in cardiac pathologies such as hypertrophy, heart failure, diabetes, dilated cardiomyopathy and myocardial infarction. Cardiac muscle isalso a target of insulin; impairment of insulin-stimulatedcardiac glucose uptake has been described in animal models ofdiabetes, obesity, and hypertension. Binding of insulin to its receptor activates the tyrosine kinaseactivity of the receptor’s ß-subunit.
This leadsto autophosphorylation as well as tyrosine phosphorylationof several insulin receptors (IR) substrates. These substrates, in turn,interact with phosphatidylinositol 3-kinase (PI3K), and stimulates Akt, a downstream serine/threoninekinase which induces glucose uptake via translocation of glucose transporter GLUT4 to the plasma membrane. Abnormalitiesin insulin signaling account for insulin resistance. Insulin resistance is an important risk factor for the development of hypertension, atherosclerotic heart disease, left ventricular hypertrophy and dysfunction, and heart failure. It reflects a disturbance of glucose metabolism and can potentially worsen metabolic efficiency of both skeletal and cardiac muscles. The exact mechanisms of cardiac insulin resistance on progression of left ventricular contractile dysfunctions are not fully elucidated.
Resveratrol (trans-3, 4’, 5-trihydroxystilbene; RSV) characterized as a phytoalexin which was first isolated from the roots of white hellebore (Veratrum grandiflorum O. Loes) in 1940. According to epidemiological studies, resveratrol has been thought to be responsible for cardiovascular benefits associated with moderate wine consumption- “The French paradox”. In addition, RSV as an estrogen receptor agonist and has anti-breast cancer effect and chemopreventive potential. Its beneficial effect on the pathogenesis of atherosclerosis has been attributed to its antioxidation and free radical-scavenging properties. Many reports suggest that RSV has been found to be a better antioxidant and free radical scavenger than ?-tocopherol, a natural antioxidant of the human body. It has been reported that RSV extends the lifespans of S. cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, implicating the potential of RSV as an anti-aging agent in treating age-related human diseases.
Interestingly, recent data have provided more insights into the effects of RSV on the metabolic syndrome. Auwerx et al. suggest that RSV protects against insulin resistance by activating SIRT1 and PGC-1. SIRT1 controls different tissue-specific metabolic processes. In muscle, SIRT1 deacetylates the coactivator PGC-1 , thereby increasing mitochondrial biogenesis and fatty acid utilization resulting in switch from glucose to fatty acid oxidation. In contrast, SIRT1 inhibit PPAR and decrease adipogenesis in white adipose tissues. Toge ther, SIRT1 modulate its activity on PGC-1 and activate mitochondrial oxidative genes that are dysregulated in metabolic disease such as obesity and lipid accumulation. Our previous studies have shown RSV possesses an insulin-like effect in both severe insulin-deficiency rats and moderate insulin-deficiency rats and the mechanism may different from insulin. In the present study, we provide novel mechanisms for protect against cardiac insulin resistance of RSV, via estrogen receptor signaling, leading to an increase of 2-DG uptake and membrane expression of GLUT 4 in high cholesterol-fructose diet induced cardiac insulin resistance and may contribute to preservation of left ventricular contractile functions.
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