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PPAR gamma agonist normalizes glomerular filtration rate, tissue levels of homocysteine, and attenuates endothelial-myocyte uncoupling in alloxan induced diabetic mice.

Rodriguez WE, Sen U, Tyagi N, Kumar M, Carneal G, Aggrawal D, Newsome J, Tyagi SC - Int. J. Biol. Sci. (2008)

Bottom Line: Endothelial-myocyte coupling was measured in cardiac rings.In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.NO levels in the LV were found inversely related to tissue Hcy levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.

ABSTRACT

Background: Homocysteine (Hcy) is an independent cardiovascular risk factor; however, in diabetes, the role of tissue Hcy leading to cardiac dysfunction is unclear.

Aims: To determine whether tissue Hcy caused endothelial-myocyte uncoupling and ventricular dysfunction in diabetes.

Methods: Diabetes was created in C57BL/6J male mice by injecting 65 mg/kg alloxan. To reverse diabetic complications, ciglitazone (CZ) was administered in the drinking water. Plasma glucose, Hcy, left ventricular (LV) tissue levels of Hcy and nitric oxide (NO) were measured. Glomerular filtration rate (GFR) was measured by inulin-FITC. Endothelial-myocyte coupling was measured in cardiac rings. In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.

Results: Plasma glucose, GFR and LV tissue Hcy were increased in diabetic mice and were normalized after CZ treatment; whereas, elevated plasma Hcy level remained unchanged with or without CZ treatment. NO levels in the LV were found inversely related to tissue Hcy levels. Attenuated endothelial-myocyte function in diabetic mice was ameliorated by CZ treatment. Cardiac relaxation, the ratio of LV wall thickness to LV diameter was decreased in diabetes, and normalized after CZ treatment.

Conclusion: CZ normalized LV tissue levels of Hcy and ameliorated endothelial-myocyte coupling; therefore, specifically suggest the association of LV tissue Hcy levels with impair endothelial-myocyte function in diabetes.

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Related in: MedlinePlus

Heart tissue levels of Hcy and nitric oxide: (A): In anesthetized mice that were treated with alloxan (A), hearts were removed at 0 (n=6), 1 (n=6) and 10 (n=6) weeks (wks). The remaining alloxan-treated mice received ciglitazone (CZ) and hearts were removed at 12 (n=6) and 16 (n=6) wks. Left ventricle (LV) homogenates were prepared. Total Hcy was extracted, separated by HPLC, and quantitated by a spectrophotometer. Hcy was expressed as ng/mg of protein. *, p<0.01 when compared to 0 wk; **, p<0.01 when compared to 10 wks. (B): Total nitrate/nitrite was measured by Griess method. Nitric oxide levels were expressed as nMole/L of LV homogenate. Identical amounts of total protein were used. *, p<0.02 when compared to 0 wk; **, p<0.005 when compared to 10 wks. Note that tissue levels of Hcy were normalized by CZ treatment.
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Figure 4: Heart tissue levels of Hcy and nitric oxide: (A): In anesthetized mice that were treated with alloxan (A), hearts were removed at 0 (n=6), 1 (n=6) and 10 (n=6) weeks (wks). The remaining alloxan-treated mice received ciglitazone (CZ) and hearts were removed at 12 (n=6) and 16 (n=6) wks. Left ventricle (LV) homogenates were prepared. Total Hcy was extracted, separated by HPLC, and quantitated by a spectrophotometer. Hcy was expressed as ng/mg of protein. *, p<0.01 when compared to 0 wk; **, p<0.01 when compared to 10 wks. (B): Total nitrate/nitrite was measured by Griess method. Nitric oxide levels were expressed as nMole/L of LV homogenate. Identical amounts of total protein were used. *, p<0.02 when compared to 0 wk; **, p<0.005 when compared to 10 wks. Note that tissue levels of Hcy were normalized by CZ treatment.

Mentions: Cardiac tissue Hcy levels were increased one week after alloxan-injection and remained elevated (Fig. 4A). Treatment with CZ ameliorated the increase in cardiac Hcy levels; however, in the present report no specific effects of CZ on Hcy metabolism were studied. Under the same conditions, NO levels inversely mirrored Hcy levels (Fig. 4B). These results and results from the previous section suggest that in diabetics, initially there is no change in plasma levels of Hcy (Fig. 2B); however, cardiac Hcy levels are increased within 1 week of diabetes induction (Fig. 4A) and are inversely related to cardiac NO generation (Fig. 4B).


PPAR gamma agonist normalizes glomerular filtration rate, tissue levels of homocysteine, and attenuates endothelial-myocyte uncoupling in alloxan induced diabetic mice.

Rodriguez WE, Sen U, Tyagi N, Kumar M, Carneal G, Aggrawal D, Newsome J, Tyagi SC - Int. J. Biol. Sci. (2008)

Heart tissue levels of Hcy and nitric oxide: (A): In anesthetized mice that were treated with alloxan (A), hearts were removed at 0 (n=6), 1 (n=6) and 10 (n=6) weeks (wks). The remaining alloxan-treated mice received ciglitazone (CZ) and hearts were removed at 12 (n=6) and 16 (n=6) wks. Left ventricle (LV) homogenates were prepared. Total Hcy was extracted, separated by HPLC, and quantitated by a spectrophotometer. Hcy was expressed as ng/mg of protein. *, p<0.01 when compared to 0 wk; **, p<0.01 when compared to 10 wks. (B): Total nitrate/nitrite was measured by Griess method. Nitric oxide levels were expressed as nMole/L of LV homogenate. Identical amounts of total protein were used. *, p<0.02 when compared to 0 wk; **, p<0.005 when compared to 10 wks. Note that tissue levels of Hcy were normalized by CZ treatment.
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Figure 4: Heart tissue levels of Hcy and nitric oxide: (A): In anesthetized mice that were treated with alloxan (A), hearts were removed at 0 (n=6), 1 (n=6) and 10 (n=6) weeks (wks). The remaining alloxan-treated mice received ciglitazone (CZ) and hearts were removed at 12 (n=6) and 16 (n=6) wks. Left ventricle (LV) homogenates were prepared. Total Hcy was extracted, separated by HPLC, and quantitated by a spectrophotometer. Hcy was expressed as ng/mg of protein. *, p<0.01 when compared to 0 wk; **, p<0.01 when compared to 10 wks. (B): Total nitrate/nitrite was measured by Griess method. Nitric oxide levels were expressed as nMole/L of LV homogenate. Identical amounts of total protein were used. *, p<0.02 when compared to 0 wk; **, p<0.005 when compared to 10 wks. Note that tissue levels of Hcy were normalized by CZ treatment.
Mentions: Cardiac tissue Hcy levels were increased one week after alloxan-injection and remained elevated (Fig. 4A). Treatment with CZ ameliorated the increase in cardiac Hcy levels; however, in the present report no specific effects of CZ on Hcy metabolism were studied. Under the same conditions, NO levels inversely mirrored Hcy levels (Fig. 4B). These results and results from the previous section suggest that in diabetics, initially there is no change in plasma levels of Hcy (Fig. 2B); however, cardiac Hcy levels are increased within 1 week of diabetes induction (Fig. 4A) and are inversely related to cardiac NO generation (Fig. 4B).

Bottom Line: Endothelial-myocyte coupling was measured in cardiac rings.In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.NO levels in the LV were found inversely related to tissue Hcy levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.

ABSTRACT

Background: Homocysteine (Hcy) is an independent cardiovascular risk factor; however, in diabetes, the role of tissue Hcy leading to cardiac dysfunction is unclear.

Aims: To determine whether tissue Hcy caused endothelial-myocyte uncoupling and ventricular dysfunction in diabetes.

Methods: Diabetes was created in C57BL/6J male mice by injecting 65 mg/kg alloxan. To reverse diabetic complications, ciglitazone (CZ) was administered in the drinking water. Plasma glucose, Hcy, left ventricular (LV) tissue levels of Hcy and nitric oxide (NO) were measured. Glomerular filtration rate (GFR) was measured by inulin-FITC. Endothelial-myocyte coupling was measured in cardiac rings. In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.

Results: Plasma glucose, GFR and LV tissue Hcy were increased in diabetic mice and were normalized after CZ treatment; whereas, elevated plasma Hcy level remained unchanged with or without CZ treatment. NO levels in the LV were found inversely related to tissue Hcy levels. Attenuated endothelial-myocyte function in diabetic mice was ameliorated by CZ treatment. Cardiac relaxation, the ratio of LV wall thickness to LV diameter was decreased in diabetes, and normalized after CZ treatment.

Conclusion: CZ normalized LV tissue levels of Hcy and ameliorated endothelial-myocyte coupling; therefore, specifically suggest the association of LV tissue Hcy levels with impair endothelial-myocyte function in diabetes.

Show MeSH
Related in: MedlinePlus