Homocysteine-dependent cardiac remodeling and endothelial-myocyte coupling in a 2 kidney, 1 clip Goldblatt hypertension mouse model.
Accumulation of interstitial collagen (fibrosis) between the endothelium and myocytes is one of the hallmarks of cardiac failure in renovascular hypertension (RVH). Renal insufficiency increases plasma homocysteine (Hcy), and levels of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are inversely related to plasma Hcy levels. We hypothesize that in RVH, accumulation of collagen between the endothelium and myocytes leads to endothelial-myocyte disconnection and uncoupling, in part, by hyperhomocysteinemia. Furthermore, we hypothesize that Hcy increases reactive oxygen species, generates nitrotyrosine, activates latent matrix metalloproteinase, and decreases the levels of endothelial nitric oxide in response to antagonizing PPAR-gamma. To create RVH in mice, the left renal artery was clipped with 0.4-mm silver wire for the 2 kidney, 1 clip (2K1C) method. Sham surgery was used as a control. To induce PPAR-gamma, 8 microg/mL ciglitazone (CZ) was administered to drinking water 2 days before surgery and continued for 4 weeks. Mice were grouped as 2K1C, sham, 2K1C+CZ, or sham+CZ (n = 6 in each group). Plasma Hcy increased 2-fold in the 2K1C-treated group (p < 0.05) as compared with the sham, and CZ had no effect on Hcy levels as compared to the 2K1C-treated group. Hcy binding in cardiac tissue homogenates decreased in the 2K1C-treated group but was substantially higher in the CZ-treated group. Cardiac reactive oxygen species levels were increased and endothelial nitric oxide were decreased in the 2K1C-treated group. Matrix metalloproteinase-2 and -9 activities were increased in the 2K1C-treated group compared with the control. Levels of cardiac inhibitor of metalloproteinase were decreased, whereas there was no change in tissue inhibitor of metalloproteinase-1 expression in the 2K1C-treated group vs. the sham-treated group. Collagen and nitrotyrosine levels were increased in the 2K1C-treated group, but mice treated with CZ showed lower levels comparatively. Cardiac transferase deoxyuridine nick-end labeling-positive cells were increased, and muscle cells were impaired in the 2K1C-treated mice vs. the sham-control mice. This was associated with decreased acetylcholine and bradykinin responses, which suggests endothelial-myocyte uncoupling in 2K1C-treated mice. Our results suggest that fibrosis between the endothelium and myocytes leads to an endothelial-myocyte disconnection and uncoupling by Hcy accumulation secondary to increased reactive oxygen species, nitrotyrosine, matrix metalloproteinase, and decreased endothelial nitric oxide in response to antagonizing PPAR-gamma.
Tyagi
Neetu
N
Department of Physiology and Biophysics, University of Louisville School of Medicine, 500 South Preston Street, Louisville, KY 40202, USA. s0tyag01@louisville.edu
Moshal
Karni S
KS
Lominadze
David
D
Ovechkin
Alexander V
AV
Tyagi
Suresh C
SC
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005355:Fibrosis / Q000473:pathology; D006710:Homocysteine / Q000502:physiology*; D006978:Hypertension, Renovascular / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007668:Kidney / Q000502:physiology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000502:physiology*
D019332:Endothelin-1; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D019715:Tissue Inhibitor of Metalloproteinase-1; D014665:Vasodilator Agents; D006710:Homocysteine; D009599:Nitroprusside; C002744:3-nitrotyrosine; D014443:Tyrosine; D003094:Collagen; D020782:Matrix Metalloproteinases; D000109:Acetylcholine; C039671:ciglitazone