Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy  

作　　者：Mark T Waddingham Amanda J Edgley Hirotsugu Tsuchimochi Darren J Kelly Mikiyasu Shirai James T Pearson 

机构地区：[1]Department of Medicine,St Vincent’s Hospital,University of Melbourne [2]Department of Physiology,Monash University [3]Department of Cardiac Physiology,National Cerebral and Cardiovascular Center Research Institute [4]Monash Biomedical Imaging Facility,Monash University [5]Australian Synchrotron

出　　处：《World Journal of Diabetes》2015年第7期943-960,共18页世界糖尿病杂志（英文版）（电子版）

基　　金：The research funding from the International Synchrotron Access Program(AS/IA133)of the Australian Synchrotron(to Pearson JT);A Grant-in-Aid for Scientific Research(#E056,26670413)from the Ministry of Education,Culture,Sports,Sciences and Technology of Japan(to Shirai M)

摘　　要：Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients.Independent of hypertension and coronary artery disease,diabetes is associated with a specific cardiomyopathy,known as diabetic cardiomyopathy(DCM).Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease,beginning early after the onset of type 1 and type 2 diabetes,ahead of left ventricular remodeling and overt diastolic dysfunction.Although the molecular pathogenesis of early DCM still remains largely unclear,activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction.Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development,relaxation and stability under pathophysiological stresses.These changes include perturbed calcium handling,suppressed activity of aerobic energy producing enzymes,altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins,reduced actin-myosin cross-bridge cycling and dynamics,and changed myofilament calcium sensitivity.In this review,we will present and discuss novel aspects of the molecular pathogenesis of early DCM,with a special focus on the sarcomeric contractile apparatus.Diabetes mellitus significantly increases the risk ofcardiovascular disease and heart failure in patients.Independent of hypertension and coronary arterydisease, diabetes is associated with a specific cardiomyopathy,known as diabetic cardiomyopathy （DCM）.Four decades of research in experimental animalmodels and advances in clinical imaging techniquessuggest that DCM is a progressive disease, beginningearly after the onset of type 1 and type 2 diabetes,ahead of left ventricular remodeling and overt diastolicdysfunction. Although the molecular pathogenesis ofearly DCM still remains largely unclear, activation ofprotein kinase C appears to be central in driving theoxidative stress dependent and independent pathwaysin the development of contractile dysfunction. Multiplesubcellular alterations to the cardiomyocyte are nowbeing highlighted as critical events in the early changesto the rate of force development, relaxation and stabilityunder pathophysiological stresses. These changes includeperturbed calcium handling, suppressed activity ofaerobic energy producing enzymes, altered transcriptionaland posttranslational modification of membrane andsarcomeric cytoskeletal proteins, reduced actin-myosincross-bridge cycling and dynamics, and changed myofilamentcalcium sensitivity. In this review, we will presentand discuss novel aspects of the molecular pathogenesisof early DCM, with a special focus on the sarcomericcontractile apparatus.

关 键 词：Diabetes PREDIABETES Insulin resistance MYOCARDIUM SARCOMERE Protein KINASE C RHO KINASE 

分 类 号：R587.2[医药卫生—内分泌]