Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes.
Cardiomyopathy is a major cause of mortality for both type 1 and 2 diabetic patients. However, experimental analysis of diabetic cardiomyopathy has focused on type 1 diabetes and there are few reports on cardiomyocyte dysfunction in the widely used type 2 diabetic model, db/db. In the current study, we assessed function in isolated ventricular myocytes from type 1 diabetic OVE26 mice and from type 2 diabetic db/db mice. When compared with their respective control strains, both diabetic models showed significant impairment in contractility, as assessed by percent peak shortening, maximal rate of contraction, and maximal rate of relaxation. The calcium decay rate was also significantly reduced in both types of diabetes, but the decrement was much greater in OVE26 myocytes, approx 50% vs only 20% in db/db myocytes. To understand the basis for slow calcium decay in diabetic myocytes and to understand the molecular basis for the quantitative difference between calcium decay in OVE26 and db/db myocytes, we measured cardiac content of the SERCA2a calcium pump. SERCA2a was significantly decreased in OVE26 diabetic myocytes but not reduced at all in db/db myocytes. The reduction of SERCA2a in OVE26 myocytes was completely prevented by overexpression of the antioxidant protein metallothionein, confirming that oxidative stress is an important component of diabetic cardiomyopathy. The current results demonstrate that though contractility is impaired in individual myocytes of db/db hearts and deficits are similar to what is seen in a severe model of type 1 diabetes, impairment in calcium reuptake is less severe, probably as a result of maintenance of normal levels of SERCA2a.
Kralik
Patricia M
PM
Ye
Gang
G
Metreveli
Naira S
NS
Shem
Xia
X
Donthi
Rajakumar V
RV
Epstein
Paul N
PN
D000818:Animals; D015153:Blotting, Western; D020013:Calcium Signaling / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D002469:Cell Separation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000473:pathology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
D005456:Fluorescent Dyes; D008668:Metallothionein; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D016257:Fura-2