Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function.
Diabetic cardiomyopathy is an important contributor to diastolic and systolic heart failure. We examined the nature and mechanism of the cardiomyopathy in Akita (Ins2(WT/C96Y)) mice, a model of genetic nonobese type 1 diabetes that recapitulates human type 1 diabetes. Cardiac function was evaluated in male Ins2WT/C96Y and their littermate control (Ins2WT/WT) mice using echocardiography and tissue Doppler imaging, in vivo hemodynamic measurements, as well as ex vivo working heart preparation. At 3 and 6 mo of age, Ins2WT/C96Y mice exhibited preserved cardiac systolic function compared with Ins2WT/WT mice, as evaluated by ejection fraction, fractional shortening, left ventricular (LV) end-systolic pressure and maximum rate of increase in LV pressure in vivo, cardiac work, cardiac power, and rate-pressure product ex vivo. Despite the unaltered systolic function, Ins2WT/C96Y mice exhibited significant and progressive diastolic dysfunction at 3 and 6 mo of age compared with Ins2WT/WT mice as assessed by tissue and pulse Doppler imaging (E-wave velocity, isovolumetric relaxation time) and by in vivo hemodynamic measurements (LV end-diastolic pressure, time constant of LV relaxation, and maximum rate of decrease in LV pressure). We found no evidence of myocardial hypertrophy or fibrosis in the Ins2WT/C96Y myocardium. Consistent with the lack of fibrosis, expression of procollagen-alpha type I, procollagen-alpha type III, and fibronectin were not increased in these hearts. Ins2WT/C96Y hearts showed significantly reduced sarcoplasmic reticulum Ca2+-ATPase 2a (cardiac sarcoplasmic reticulum Ca2+ pump) levels, elevated beta-myosin heavy chain isoform, increased long-chain fatty acids, and triacylglycerol with evidence of lipotoxicity, as indicated by a significant rise in ceramide, diacylglycerol, and lipid deposits in the myocardium. Consistent with metabolic perturbation, and a switch to fatty acid oxidation from glucose oxidation in Ins2WT/C96Y hearts, expression of mitochondrial long-chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase isoform 4 were increased. Insulin treatment reversed the diastolic dysfunction, the elevated B-type natriuretic peptide and beta-myosin heavy chain, and the reduced sarcoplasmic reticulum Ca2+-ATPase 2a levels with abolition of cardiac lipotoxicity. We conclude that early type 1 diabetic cardiomyopathy is characterized by diastolic dysfunction associated with lipotoxic cardiomyopathy with preserved systolic function in the absence of interstitial fibrosis and hypertrophy.
Department of Physiology, Rm 474, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Ratnadeep
R
Basu
Gavin Y
GY
Oudit
Xiuhua
X
Wang
Liyan
L
Zhang
John R
JR
Ussher
Gary D
GD
Lopaschuk
Zamaneh
Z
Kassiri
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002518:Ceramides / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003971:Diastole; D004075:Diglycerides / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D018619:Echocardiography, Doppler, Pulsed; D005227:Fatty Acids / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013318:Stroke Volume; D013599:Systole; D014280:Triglycerides / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017725:Ventricular Pressure
C506948:Atp2a2 protein, rat; D001786:Blood Glucose; D002518:Ceramides; D004075:Diglycerides; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; C000594638:MYH7 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014280:Triglycerides; D020097:Natriuretic Peptide, Brain; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D017346:Protein Serine-Threonine Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains