Atsuko Nose

Angiotensin AT1 and AT2 Receptors Differentially Regulate Angiopoietin-2 and Vascular Endothelial Growth Factor Expression and Angiogenesis by Modulating Heparin Binding–Epidermal Growth Factor (EGF)–Mediated EGF Receptor Transactivation

Angiotensin II (Ang II)-mediated signals are transmitted via heparin binding epidermal growth factor (EGF)-like growth factor (HB-EGF) release followed by transactivation of EGF receptor (EGFR). Although Ang II and HB-EGF induce angiogenesis, their link to the angiopoietin (Ang)-Tie2 system remains undefined. We tested the effects of Ang II on Ang1, Ang2, or Tie2 expression in cardiac microvascular endothelial cells expressing the Ang II receptors AT(1) and AT(2). Ang II significantly induced Ang2 mRNA accumulations without affecting Ang1 or Tie2 expression, which was inhibited by protein kinase C inhibitors and by intracellular Ca(2+) chelating agents. Ang II transactivated EGFR via AT(1), and inhibition of EGFR abolished the induction of Ang2. Ang II caused processing of pro-HB-EGF in a metalloproteinase-dependent manner to stimulate maturation and release of HB-EGF. Neutralizing anti-HB-EGF antibody blocked EGFR phosphorylation by Ang II. Ang II also upregulated vascular endothelial growth factor (VEGF) expression in an HB-EGF/EGFR-dependent manner. AT(2) inhibited AT(1)-mediated Ang2 expression and phosphorylation of EGFR. In an in vivo corneal assay, AT(1) induced angiogenesis in an HB-EGF-dependent manner and enhanced the angiogenic activity of VEGF. Although neither Ang2 nor Ang1 alone induced angiogenesis, soluble Tie2-Fc that binds to angiopoietins attenuated AT(1)-mediated angiogenesis. These findings suggested that (1) Ang II induces Ang2 and VEGF expression without affecting Ang1 or Tie2 and (2) AT(1) stimulates processing of pro-HB-EGF by metalloproteinases, and the released HB-EGF transactivates EGFR to induce angiogenesis via the combined effect of Ang2 and VEGF, whereas AT(2) attenuates them by blocking EGFR phosphorylation. Thus, Ang II is involved in the VEGF-Ang-Tie2 system via HB-EGF-mediated EGFR transactivation, and this link should be considerable in pathological conditions in which collateral blood flow is required.

Angiotensin II type 2 receptor inhibits epidermal growth factor receptor transactivation by increasing association of SHP-1 tyrosine phosphatase

Angiotensin (Ang) II has 2 major receptor isoforms, Ang type 1 (AT1) and Ang type (AT2). AT1 transphosphorylates epidermal growth factor receptor (EGFR) to activate extracellular signal–regulated kinase (ERK). Although AT2 was shown to inactivate ERK, the action of AT2 on EGFR activation remains undefined. Using AT2-overexpressing vascular smooth muscle cells from AT2 transgenic mice, we studied these undefined actions of AT2. Maximal ERK activity induced by Ang II was increased 1.9- and 2.2-fold by AT2 inhibition, which was abolished by orthovanadate but not okadaic acid or pertussis toxin. AT2 inhibited AT1-mediated EGFR tyrosine phosphorylation by 63%. The activity of SHP-1 tyrosine phosphatase was significantly upregulated 1 minute after AT2 stimulation and association of SHP-1 with EGFR was increased, whereas AT2 failed to tyrosine phosphorylate SHP-1. Stable overexpression of SHP-1–dominant negative mutant completely abolished AT2-mediated inhibition of EGFR and ERK activation. AT1-mediated c-fos mRNA accumulation was attenuated by 48% by AT2 stimulation. Induction of fibronectin gene containing an AP-1 responsive element in its 5′-flanking region was decreased by 37% after AT2 stimulation, corresponding to the results of gel mobility assay with the AP-1 sequence of fibronectin as a probe. These findings suggested that AT2 inhibits ERK activity by inducing SHP-1 activity, leading to decreases in AP-1 activity and AP-1–regulated gene expression, in which EGFR dephosphorylation plays an important role via association of SHP-1.

Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis.

In most cases of systemic lupus erythematosus (SLE), glomerular lesions are the main renal complication. Although tubulointerstitial lesions are often associated with severe glomerular lesions, predominant or isolated tubulointerstitial injury in the presence of minimal glomerular abnormalities with SLE, so-called predominant tubulointerstitial lupus nephritis, is rare. Only ten cases are reported in the English literature. Herein, we describe the case of a 64-year-old man with SLE who presented with acute renal deterioration attributable to acute tubulointerstitial nephritis. Renal biopsy showed diffuse infiltration of inflammatory mononuclear cells in the interstitium and tubulitis without significant glomerular lesions. Immunofluorescence study revealed positive staining for IgG, C3, and C1q along the renal tubular basement membrane (TBM). Electron microscopy also showed electron-dense deposits in the TBM. Other causes of tubulointerstitial injury, such as drug use and infection, were ruled out. Taking these findings together with the presence of antitubular basement membrane antibody, predominant tubulointerstitial lupus nephritis was diagnosed. Treatment with oral corticosteroids for 6 weeks improved renal function. Even after tapering of the corticosteroid, renal function and serological markers of SLE activity have remained stable in this patient for more than 12 months.

Comparison of the Effects of Quinapril and Losartan on Carotid Artery Intima-Media Thickness in Patients with Mild-to-Moderate Arterial Hypertension

Background: Ultrasonographic evidence of increased carotid intima-media thickness (IMT) is known to be associated with generalized atherosclerosis. Therapeutic blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors reportedly reduces carotid IMT in humans. However, there has been no head-to-head comparison of the effects of ACE inhibitor and angiotensin receptor blocker (ARB), a newer type of RAS inhibitor, on carotid IMT. Methods: 57 hypertensive patients were randomly assigned to treatment with one of two antihypertensive drugs: ACE inhibitor (quinapril; n = 25, group Q) or ARB (losartan; n = 18, group L). Results: After 1 year of treatment, a similar decrease in mean blood pressure was observed in all groups. Carotid IMT was decreased significantly in group Q (10% decrease, p < 0.05) but did not change in group L. There were no significant changes in other atherosclerotic factors between these two groups. Conclusion: Our findings suggest that the antiatherosclerotic effect of quinapril is more potent than that of losartan in hypertensive patients. This effect appears unrelated to the drug’s antihypertensive action or to traditional atherosclerotic factors.

'Takotsubo' cardiomyopathy in a maintenance hemodialysis patient.

Abstract:  An 84‐year‐old woman undergoing maintenance hemodialysis presented with chest discomfort lasting several days and electrocardiographic abnormalities. She had stopped smoking 2 weeks earlier and was experiencing irritability. Upon admission, electrocardiography showed ST‐segment elevation in leads I, II, aVF, and V2‐6 and an abnormal Q wave in leads II, III, and aVF. Ultrasound cardiography showed left ventricular anteroapical akinesia and basal hyperkinesia. The chest discomfort disappeared without specific therapy. During hospital days 1–5, the ST‐segment elevation gradually improved. Giant negative T waves then developed. The left ventricular asynergy resolved by day 8. Radionuclide imaging with iodine‐123‐beta‐methyl‐p‐iodophenyl pentadecanoic acid, but not with technetium‐99 m‐sestamibi, showed an apical defect. Elective coronary angiography showed no stenosis. ‘Takotsubo’ cardiomyopathy was diagnosed. After discharge, the patient continued regular dialysis without cardiac symptoms. We concluded that endogenously activated sympathetic nerve action in hemodialysis patients, especially those under emotional or physical stress, might be a causative factor for Takotsubo cardiomyopathy.