Ick-Mo Chung

Immobilization stress induces endothelial dysfunction by oxidative stress via the activation of the angiotensin II/its type I receptor pathway

OBJECTIVE Psychological stress has been shown to contribute to the development of atherosclerosis; however its underlying mechanism has not been clearly elucidated. We here studied the mechanism by which immobilization stress causes endothelial dysfunction with specific aim of identifying the role of angiotensin II and its type I (AT(1)) receptor signaling pathway. METHODS AND RESULTS Rats (n=30) were subjected to immobilization stress (120 min/day) for 14 days using a restrainer. During immobilized period, rats were orally administrated with or without the angiotensin converting enzyme (ACE) inhibitor ramipril (3 mg/kg/day, n=10) or AT(1) receptor inhibitor losartan (9 mg/kg/day, n=10). Immobilization significantly increased systolic blood pressure and decreased acetylcholine-induced ex vivo relaxation of arteries compared with those of control animals (n=10). Immobilization increased the plasma levels of angiotensin II and ACE activity that were inhibited by treatment with ramipril, but not losartan. Furthermore, immobilization increased the plasma level of malondialdehyde and expression of gp91(phox) and Rho-associated kinase-1 in arteries, and decreased the arterial eNOS mRNA and oxidized products of NO (nitrite plus nitrate). These functional and biochemical alterations induced by immobilization were significantly reversed by administration of ramipril or losartan. CONCLUSIONS Immobilization stress induces vascular oxidative stress by activating the angiotensin II/AT(1) receptor signaling pathway, thereby provoking endothelial dysfunction which can contribute to the development of atherosclerosis and hypertension.

Catheter-based adenovirus-mediated local intravascular gene delivery of a soluble TGF-β type II receptor using an Infiltrator in porcine coronary arteries: efficacy and complications

Enhanced extracellular matrix (ECM) accumulation is an important finding in human restenotic arterial neointima after angioplasty. Transforming growth factor β1(TGF-β1) is known to regulate the synthesis and turnover of a variety of ECM components, and may play an important role in restenosis. Recombinant adenoviral vector expressing an ectodomain of the TGF-β type II receptor fused to the human immunoglobulin Fc portion (AdTβ-ExR) inhibits the action of TGF-β probably either by adsorbing TGF-β or by acting as a dominant negative receptor. We carried out a catheter-based local adenovirus mediated gene delivery using an Infiltrator in porcine coronary arteries to know the pattern of gene expression, efficacy and procedural complications. Twenty four coronary arteries in 13 pigs were used for intravascular gene delivery by intramural injection with either AdTβ-ExR or adenovirus expressing b-galactosidase (AdCALacZ). Direct immunofluorescent staining and reverse transcription polymerase chain reaction (RTPCR) were used for detection of type II TGF-β receptor and its mRNA respectively. X-Gal histochemistry was performed to identify b-galactosidase. Both soluble TGF-β receptor and b-galactosidase were expressed locally in the media and adventita at injected arterial segments without any significant dissemination to remote area. Intravascular gene transfection performed with various titer of each adenoviral vector showed that AdTβ-ExR of 5x10(8) pfu and AdCALacZ of 2.5 x 10(8) pfu were the minimum titer for the expression of each transgene. Infiltration of CD3 positive T cells was detected by immunohistochemical staining in the area of each transgene expression, and tends to decrease over time after gene delivery. Pathological study of 24 treated arteries showed complications such as disruption of external elastic lamina with hemorrhage (n = 4), minimal disruption of internal elastic lamina and endothelial layer, and medial thickening. In conclusion, catheter-based local intravascular gene delivery of adenoviral vector is feasible and effective in a selected artery, but must be undertaken with caution due to possible lethal complications. Local delivery of soluble TGF-β type II receptor in this way may provide an effective intravascular gene therapy to inhibit TGF-β signal pathway without any significant systemic side effect.

Prognostic Impact of Early ST-Segment Resolution and Biochemical Markers in Patients With ST-Elevation Myocardial Infarction

Refer to the page 372-378 Considerable variability exists for the reported mortality risk among patients with ST-elevation myocardial infarction (STEMI) and who are treated with primary percutaneous coronary intervention (PCI). The diversity in the clinical out comes for these patients challenges the physician at each step: risk stratification, planning the treatment and monitoring the response to PCI. In this regard, the current guidelines for the treatment of patients with acute coronary syndrome (ACS) recommend risk stratification using a variety of clinical vari ables. Clinical variables such as biomarkers, electrocardiography (ECG), and the imaging modalities have been studied for whether these variables may improve the risk assessment and clinical care. The standard 12-lead ECG has been used as the single most important diagnostic tool for the evaluation of ACS. Measurement via ECG is very useful and informative for determining the quality of reperfusion in patients with acute STEMI. The degree of ST segment deviation also confers prognostic information. 1) Since it was first documented in 1971 in an animal study that the magnitude of ST segment elevation was well correlated well with depressed myocardial creatine kinase activity as well as myocardial necrosis, 2) the degree of ST segment elevation has been used as an