Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats.

To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7) mol/l AM; LZ, -85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.

[1]  K. Macleod,et al.  Age-dependent changes in blood pressure and arterial reactivity in obese Zucker rats. , 2003, European journal of pharmacology.

[2]  M. Omata,et al.  Hypoxia-induced adrenomedullin production in the kidney. , 1999, Kidney international.

[3]  D. Heudes,et al.  Increased SMC proliferation after endothelial injury in hyperinsulinemic obese Zucker rats. , 1994, The American journal of physiology.

[4]  U. Laufs,et al.  3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27 Kip1 * , 1999, The Journal of Biological Chemistry.

[5]  Y. Ouchi,et al.  Augmented Contractile Function and Abnormal Ca2+ Handling in the Aorta of Zucker Obese Rats With Insulin Resistance , 1996, Diabetes.

[6]  T. Sasaki,et al.  Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction. , 1992, The Journal of biological chemistry.

[7]  S. Lohmann,et al.  Cyclic GMP-dependent Protein Kinase Signaling Pathway Inhibits RhoA-induced Ca2+ Sensitization of Contraction in Vascular Smooth Muscle* , 2000, The Journal of Biological Chemistry.

[8]  A. Chobanian,et al.  Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. , 1990, Hypertension.

[9]  澤田 直樹.  Inhibition of Rho-Associated Kinase Results in Suppression of Neointimal Formation of Balloon-Injured Arteries , 2001 .

[10]  A. Dumont,et al.  Hyperinsulinemia superimposed on insulin resistance does not elevate blood pressure. , 2001, American journal of hypertension.

[11]  SubrinaJesmin,et al.  Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats , 2003 .

[12]  M. Leon,et al.  Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. A serial intravascular ultrasound study. , 1997, Circulation.

[13]  P. Tsao,et al.  Nitric oxide regulates monocyte chemotactic protein-1. , 1997, Circulation.

[14]  U. Laufs,et al.  Post-transcriptional Regulation of Endothelial Nitric Oxide Synthase mRNA Stability by Rho GTPase* , 1998, The Journal of Biological Chemistry.

[15]  B. Buckley,et al.  Statins do more than just lower cholesterol , 1996, The Lancet.

[16]  R W Alexander,et al.  Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: A potential link between the renin-angiotensin system and atherosclerosis. , 1999, Circulation.

[17]  K. Walsh,et al.  HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. , 2003, Cardiovascular research.

[18]  E. Topol,et al.  Neointimal Hyperplasia After Arterial Injury Is Increased in a Rat Model of Non–Insulin-Dependent Diabetes Mellitus , 2001, Circulation.

[19]  R. Busse,et al.  Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation , 1999, Nature.

[20]  A. Zeiher,et al.  Double-Edged Role of Statins in Angiogenesis Signaling , 2002, Circulation research.

[21]  C. Kahn,et al.  Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. , 1997, The Journal of clinical investigation.

[22]  M. Morissette,et al.  Increased Expression and Activity of RhoA Are Associated With Increased DNA Synthesis and Reduced p27Kip1 Expression in the Vasculature of Hypertensive Rats , 2001, Circulation research.

[23]  W. Sessa,et al.  Regulation of endothelium-derived nitric oxide production by the protein kinase Akt , 1999, Nature.

[24]  I. Shiojima,et al.  The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. , 2000, Nature Medicine.

[25]  G. Williams,et al.  The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats. , 1999, Diabetes.

[26]  R. Chisholm,et al.  Simvastatin modulates angiotensin II signaling pathway by preventing Rac1-mediated upregulation of p27. , 2004, Journal of the American Society of Nephrology : JASN.

[27]  H. Nishimatsu,et al.  Adrenomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway in Rat Aorta , 2001, Circulation research.

[28]  A. Hall,et al.  Role of guanine nucleotide-binding proteins--ras-family or trimeric proteins or both--in Ca2+ sensitization of smooth muscle. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Corey,et al.  Lovastatin inhibits platelet-derived growth factor (PDGF) stimulation of phosphatidylinositol 3-kinase activity as well as association of p85 subunit to tyrosine-phosphorylated PDGF receptor. , 1993, The Journal of biological chemistry.

[30]  T. Fujita,et al.  Statins inhibit osteoblast migration by inhibiting Rac-Akt signaling. , 2004, Biochemical and biophysical research communications.

[31]  C. Kahn,et al.  Cross-talk between the insulin and angiotensin signaling systems. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Omata,et al.  Reentry into the Cell Cycle of Contact-inhibited Vascular Endothelial Cells by a Phosphatase Inhibitor , 2000, The Journal of Biological Chemistry.

[33]  M. Igarashi,et al.  Candesartan Inhibits Carotid Intimal Thickening and Ameliorates Insulin Resistance in Balloon-Injured Diabetic Rats , 2001, Hypertension.

[34]  S. Corey,et al.  Lovastatin disrupts early events in insulin signaling: a potential mechanism of lovastatin's anti-mitogenic activity. , 1994, Biochemical and biophysical research communications.

[35]  K. Kangawa,et al.  Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. , 1993, Biochemical and biophysical research communications.

[36]  YasushiImai,et al.  Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene , 2001 .