Ang II increases gp91phox expression in EPC, which may contribute to oxidative stress, as evidenced by peroxynitrite formation. Ang II accelerates the onset of EPC senescence via increased oxidative stress, which may be related to telomerase inactivation. In addition, Ang II-induced EPC senescence leads to the impairment of proliferative activity.

novel cardiac syndrome known as 'tako-tsubo' cardiomyopathy or 'transient left ventricular apical ballooning' and which mimics acute myocardial infarction has recently been proposed by Japanese cardiologists. 1,2 It is characterized by (1) acute onset and reversible left ventricular (LV) apical wall motion abnormalities (ballooning) with chest symptoms, (2) electrocardiographic (ECG) changes (ie, ST elevation), (3) minimal myocardial enzymatic release, and (4) no significant stenosis on coronary angiography. Emotional or physical stress usually precedes the attack, but the precise etiology remains to be elucidated. Myocardial ischemia -reperfusion because of microvascular spasm or a direct cardiac effect of catecholamines might be the cause of this transient abnormality of LV wall motion, yet clinical approaches have been limited in detecting its pathogenesis. To understand the causal relation between stress and this syndrome, investigations using a whole animal model are fundamental. We previously reported that immobilization (IMO) of the rat, a useful animal model of emotional stress, 3 produced reversible elevation of the ST segment on ECG, which was normalized by pretreatment with -adrenoceptor blockers, but not by potent coronary vasodilators such as a calcium channel blocker or nitroglycerin. 4 In the present study, we used left ventriculography (LVG) in the rat to examine stress-induced abnormalities of LV wall motion.A polyethylene catheter (PE50, Becton Dickinson, Sparks, MD, USA) was inserted into the left ventricle via the common carotid artery of adult female Wistar rats (n=10; 250-300 g). Under anesthesia induced with pentobarbital (40 mg/kg), 1 ml of contrast medium (Iopamidol 370, Schering Ag, Berlin, Germany) was injected and LVG was performed (controls) using the digital subtraction system (DSA) (SERIES 9600, OEC Medical Systems Inc, Salt Lake City, UT, USA). LVG was recorded at 30 frames/s, and evaluated independently by 2 observers. The margins of the LV images were traced, and the end-systolic or end-diastolic LV areas were also evaluated using the NIH image. Percent contraction was determined as 100 × (end-diastolic area -end-systolic area) / end-diastolic area. Statistical analysis was performed by one-way ANOVA followed by Fisher's protected least significant difference test, using StatView software (Abacus Concepts, Berkeley, CA, USA).The next day, the rats were exposed to IMO stress for up to 30 min by securing the rat on its back to a board using adhesive tape, and LVG was performed without anesthesia. All animal manipulations were approved by Wakayama Medical University Animal Care and Use Committee.In response to stress, generalized LV hypokinesis was observed in 4 cases and apical ballooning was observed in 4 cases (Fig 1). The other 2 cases were judged to be unaffected by stress (Fig 2). The following day, rats that had shown LV hypokinesis (n=3) or apical ballooning (n=3) were again subjected to IMO stress after pretreatment with an -adrenoceptor blocker, amosulalol hydrochloride (...

1. Recent studies have revealed an association between coronary risk factors and both the number and function of bone marrow-derived endothelial progenitor cells (EPC). We investigated the effect of oxidized low-density lipoprotein (ox-LDL) on the senescence of EPC, leading to cellular dysfunction. 2. Endothelial progenitor cells were isolated from human peripheral blood and characterized. The exposure of cultured EPC to ox-LDL (10 microg/mL) significantly accelerated the rate of senescence compared with control during 20 days in culture as determined by acidic beta-galactosidase staining. Oxidized LDL-induced EPC senescence was significantly inhibited by pretreatment with either lectin-like ox-LDL receptor-1 (LOX-1) antibody (Ab) or atorvastatin (P < 0.01). 3. Because cellular senescence is critically influenced by telomerase, which elongates telomeres, we measured telomerase activity using a polymerase chain reaction-ELISA-based assay. Oxidized LDL significantly diminished telomerase activity to approximately 50%, an effect that was significantly abolished by pretreatment with either LOX-1 Ab or atorvastatin (P < 0.01). 4. We examined whether ox-LDL-induced EPC senescence translates into EPC dysfunction. An MTS assay disclosed an inhibitory effect of ox-LDL on EPC proliferation. In a Matrigel assay, EPC treated with ox-LDL were less likely to participate in network formation compared with controls. 5. In conclusions, ox-LDL accelerates the onset of EPC senescence, which may be related to telomerase inactivation. Oxidized LDL-induced EPC senescence leads to the impairment of proliferative capacity and network formation.