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Cardiac β-Adrenoceptor Expression Is Reduced in Zucker Diabetic Fatty Rats as Type-2 Diabetes Progresses.

Haley JM, Thackeray JT, Thorn SL, DaSilva JN - PLoS ONE (2015)

Bottom Line: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed.In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6).At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%).

View Article: PubMed Central - PubMed

Affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.

ABSTRACT

Objectives: Reduced cardiac β-adrenoceptor (β-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac β-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac β-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats.

Methods: Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of β-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured.

Results: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced β-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6). At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function.

Conclusions: Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and β1- and β2-AR expression are inversely correlated with the progression of type-2 diabetes.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of cardiac β-AR subtypes.Expression relative to ZL of cardiac β1-AR (A), β2-AR (B), and β3-AR (C) at 10 and 16 weeks of age. Representative 10 week blots for cardiac β1-AR (D), β2-AR (E), and β3-AR (E). Representative 16 week blots for cardiac β1-AR (F), β2-AR (G), and β3-AR (H). Relative expression compared with ZL is combined from at least 3 Western blot analyses. n = 3 per group. Data are mean ± SD. *p<0.05 vs ZL, Student’s t-test.
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pone.0127581.g003: Western blot analysis of cardiac β-AR subtypes.Expression relative to ZL of cardiac β1-AR (A), β2-AR (B), and β3-AR (C) at 10 and 16 weeks of age. Representative 10 week blots for cardiac β1-AR (D), β2-AR (E), and β3-AR (E). Representative 16 week blots for cardiac β1-AR (F), β2-AR (G), and β3-AR (H). Relative expression compared with ZL is combined from at least 3 Western blot analyses. n = 3 per group. Data are mean ± SD. *p<0.05 vs ZL, Student’s t-test.

Mentions: Western blotting at 10 weeks of age showed no difference in cardiac β1-AR expression between ZL and ZDF animals, but by 16 weeks β1-AR expression was reduced 32±16 in ZDF (Fig 3A,3D and 3G). ZDF cardiac β2-AR expression was 24±10% lower at 10 weeks and was decreased by 32±14% at 16 weeks relative to ZL (Fig 3B,3E and 3H). Cardiac β3-AR expression exhibited modest but significant elevations in ZDF animals of 8±6% at 10 weeks and 12±9% at 16 weeks of age (Fig 3C,3F and 3I).


Cardiac β-Adrenoceptor Expression Is Reduced in Zucker Diabetic Fatty Rats as Type-2 Diabetes Progresses.

Haley JM, Thackeray JT, Thorn SL, DaSilva JN - PLoS ONE (2015)

Western blot analysis of cardiac β-AR subtypes.Expression relative to ZL of cardiac β1-AR (A), β2-AR (B), and β3-AR (C) at 10 and 16 weeks of age. Representative 10 week blots for cardiac β1-AR (D), β2-AR (E), and β3-AR (E). Representative 16 week blots for cardiac β1-AR (F), β2-AR (G), and β3-AR (H). Relative expression compared with ZL is combined from at least 3 Western blot analyses. n = 3 per group. Data are mean ± SD. *p<0.05 vs ZL, Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4440709&req=5

pone.0127581.g003: Western blot analysis of cardiac β-AR subtypes.Expression relative to ZL of cardiac β1-AR (A), β2-AR (B), and β3-AR (C) at 10 and 16 weeks of age. Representative 10 week blots for cardiac β1-AR (D), β2-AR (E), and β3-AR (E). Representative 16 week blots for cardiac β1-AR (F), β2-AR (G), and β3-AR (H). Relative expression compared with ZL is combined from at least 3 Western blot analyses. n = 3 per group. Data are mean ± SD. *p<0.05 vs ZL, Student’s t-test.
Mentions: Western blotting at 10 weeks of age showed no difference in cardiac β1-AR expression between ZL and ZDF animals, but by 16 weeks β1-AR expression was reduced 32±16 in ZDF (Fig 3A,3D and 3G). ZDF cardiac β2-AR expression was 24±10% lower at 10 weeks and was decreased by 32±14% at 16 weeks relative to ZL (Fig 3B,3E and 3H). Cardiac β3-AR expression exhibited modest but significant elevations in ZDF animals of 8±6% at 10 weeks and 12±9% at 16 weeks of age (Fig 3C,3F and 3I).

Bottom Line: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed.In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6).At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%).

View Article: PubMed Central - PubMed

Affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.

ABSTRACT

Objectives: Reduced cardiac β-adrenoceptor (β-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac β-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac β-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats.

Methods: Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of β-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured.

Results: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced β-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6). At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function.

Conclusions: Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and β1- and β2-AR expression are inversely correlated with the progression of type-2 diabetes.

No MeSH data available.


Related in: MedlinePlus