CSB327 Lecture 17 Summary

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University of Toronto St. George
Cell and Systems Biology
Maurice Ringuette

Lecture 17 - Heart failure o Functionally insufficient pumping capacity of blood to meet metabolic needs of tissue o Underlying mechanism  Cardiac ischemia  Hypertension  Diabetic cardiomyopathy - Diabetic cardiomyopathy  Diabetes mellitus  Diastolic abnormalities  Decrease in left ventricular ejection  Heart failure o Diabetic cardiomyopathy is accelerated by diabetes and hyperglycemia - Cardiomyocyte function is intimately tied to the interstitial collagen I matrix o Collagen fibrils are properly oriented to promote efficient contractions o Cardiac hypertrophy and dysfunction, in association with fibrosis, is a common complication in diabetes - ECM components of the myocardium o 25% cardiac myocytes  LV  muscle sheet layers  endomysium  cardiac myocytes + collagen + capillaries o 40% cardiac fibroblasts - Diabetes  Hyperglycemia  Glycation o Diabetes is a chronic disease in which there are high levels of sugar in the blood  Lack of insulin due to loss of beta cells in the pancreas (Type I, juvenile onset)  Insulin deficiency  Target cells are insensitive to insulin (Type II, adult onset)  Insulin resistant o Hyperglycemia is high blood sugar  Lead to degradation of glucose that results in the formation of highly reactive sugar intermediates  Methylglyoxal (MGO) is a highly reactive dicarbonyl o Reacts with Lys and Arg and thiol groups of Cys o Forms intermediate glycation products o Eventually transforms into advanced glycation end products (AGEs)  AGEs form as a result of chemical reactions that occur after the initial glycation event o Requires short incubation times, making it easier to carry out in vitro studies  Glycosylation is an enzymatic addition of sugars to protein (controlled, physiological)  Glycation is a non-enzymatic addition of sugar to protein (uncontrolled, pathological) o Glycation accumulates on long-lived ECM proteins like collagen I  Glycation modification of collagen I by MGO has several potential consequences  Integrin binding sites or epitopes (RGD and GFOGER) are blocked
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