Impaired cardiac functional reserve in type 2 diabetic db/db mice is associated with metabolic, but not structural, remodelling.
OBJECTIVE
To identify the initial alterations in myocardial tissue associated with the early signs of diabetic cardiac haemodynamic dysfunction, we monitored changes in cardiac function, structural remodelling and gene expression in hearts of type 2 diabetic db/db mice.


METHODS
Cardiac dimensions and function were determined echocardiographically at 8, 12, 16 and 18 weeks of age. Left ventricular pressure characteristics were measured at 18 weeks under baseline conditions and upon dobutamine infusion.


RESULTS
The db/db mice were severely diabetic already at 8 weeks after birth, showing elevated fasting blood glucose levels and albuminuria. Nevertheless, echocardiography revealed no significant changes in cardiac function up to 18 weeks of age. At 18 weeks of age, left ventricular pressure characteristics were not significantly different at baseline between diabetic and control mice. However, dobutamine stress test revealed significantly attenuated cardiac inotropic and lusitropic responses in db/db mice. Post-mortem cardiac tissue analyses showed minor structural remodelling and no significant changes in gene expression levels of the sarcoplasmic reticulum calcium ATPase (SERCA2a) or beta1-adrenoceptor (beta1-AR). Moreover, the phosphorylation state of known contractile protein targets of protein kinase A (PKA) was not altered, indicating unaffected cardiac beta-adrenergic signalling activity in diabetic animals. By contrast, the substantially increased expression of uncoupling protein-3 (UCP3) and angiopoietin-like-4 (Angptl4), along with decreased phosphorylation of AMP-activated protein kinase (AMPK) in the diabetic heart, is indicative of marked changes in cardiac metabolism.


CONCLUSIONS
db/db mice show impaired cardiac functional reserve capacity during maximal beta-adrenergic stimulation which is associated with unfavourable changes in cardiac energy metabolism.
Daniels
A
A
Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
van Bilsen
M
M
Janssen
B J A
BJ
Brouns
A E
AE
Cleutjens
J P M
JP
Roemen
T H M
TH
Schaart
G
G
van der Velden
J
J
van der Vusse
G J
GJ
van Nieuwenhoven
F A
FA
D000318:Adrenergic beta-Agonists; D000367:Age Factors; D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004280:Dobutamine; D015150:Echocardiography, Doppler; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D016277:Ventricular Function, Left / Q000235:genetics; D017725:Ventricular Pressure; D020257:Ventricular Remodeling / Q000235:genetics
D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D004280:Dobutamine