Effect of sex on recovery of ejection fraction in patients with anterior ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

OBJECTIVES: Myocardial necrosis after ST-segment elevation myocardial infarction (STEMI) can cause left ventricular systolic dysfunction, which has been associated with poor outcomes. Some authors have reported that women have higher mortality rates after primary percutaneous coronary intervention (PCI), but differences between the sexes with regard to recovery of ejection fraction (EF) in patients with STEMI receiving primary PCI have not been evaluated. We aimed to assess the effect of sex on EF recovery in patients with anterior wall STEMI after primary PCI. PATIENTS AND METHODS: A total of 202 consecutive patients (134 men) admitted due to anterior wall STEMI to our hospital over 44 months were evaluated. All patients were taken directly to the Cardiac Catheterization Laboratory for primary PCI. Baseline clinical variables were collected, and left ventricular ejection fraction (LVEF) was measured by echocardiography using the biplane Simpson model on the day after PCI and 6 months later. RESULTS: Women were significantly older than men (66.9±8.5 vs. 59.5±9.8, P<0.001). They also had a higher prevalence of hypertension and were less likely to be smokers compared with men. The time from symptom onset to hospital admission was longer in women than in men (8.9±3.0 vs. 7.8±2.4 h, P=0.048). At 1 day and 6 months after PCI, the EF was lower in women compared with men. The difference in values between 1 day and 6 months after PCI was also significantly lower in women compared with men (3.0±2.3 vs. 5.8±3.7, P<0.001). Multivariable linear regression analyses showed that being female was a significant predictor of LVEF recovery, even after adjustment for important clinical covariates. CONCLUSION: These data suggest that being female is an independent determinant of LVEF recovery in patients with anterior myocardial infarction after primary PCI.

Functional blockage of EMMPRIN ameliorates atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Extracellular matrix metalloproteinase inducer (EMMPRIN), a 58-kDa cell surface glycoprotein, has been identified as a key receptor for transmitting cellular signals mediating metalloproteinase activities, as well as inflammation and oxidative stress. Clinical evidence has revealed that EMMPRIN is expressed in human atherosclerotic plaque; however, the relationship between EMMPRIN and atherosclerosis is unclear. To evaluate the functional role of EMMPRIN in atherosclerosis, we treated apolipoprotein E-deficient (ApoE(-/-)) mice with an EMMPRIN function-blocking antibody. METHODS AND RESULTS: EMMPRIN was found to be up-regulated in ApoE(-/-) mice fed a 12-week high-fat diet in contrast to 12 weeks of normal diet. Administration of a function-blocking EMMPRIN antibody (100 µg, twice per week for 4 weeks) to ApoE(-/-) mice, starting after 12 weeks of high-fat diet feeding caused attenuated and more stable atherosclerotic lesions, less reactive oxygen stress generation on plaque, as well as down-regulation of circulating interleukin-6 and monocyte chemotactic protein-1 in ApoE(-/-) mice. The benefit of EMMPRIN functional blockage was associated with reduced metalloproteinases proteolytic activity, which delayed the circulating monocyte transmigrating into atherosclerotic lesions. CONCLUSION: EMMPRIN antibody intervention ameliorated atherosclerosis in ApoE(-/-) mice by the down-regulation of metalloproteinase activity, suggesting that EMMPRIN may be a viable therapeutic target in atherosclerosis.

Angiotensin II induces EMMPRIN expression in THP-1 macrophages via the NF-kappaB pathway.

BACKGROUND: Recent studies on atherosclerosis showed that an inducer of MMPs, EMMPRIN, is highly expressed in human atheromas. This suggested the important role of EMMPRIN in the stability of atherosclerotic plaques. Angiotensin II, one of the main functional peptides in the renin-angiotensin system, is involved in the advancement of atherosclerosis. We evaluated the effect of angiotensin II on EMMPRIN expression in THP-1 macrophages, and postulated the potential mechanisms underlying its effects. METHODS AND RESULTS: We established THP-1 macrophages using PMA. The effect of angII on EMMPRIN expression in THP-1 macrophages was then investigated. Results from analyses of RT-PCR and western blotting showed that angII could upregulate EMMPRIN expression. This was mediated via the AT1R, but not the AT2R. The NF-kappaB inhibitor PDTC and P65 RNAi treatment could suppress the effect of angII on EMMPRIN, suggesting the involvement of the NF-kappaB pathway. A gelatin zymography assay showed that MMP-9 activity was related to EMMPRIN expression. CONCLUSION: AngII upregulates the expression of EMMPRIN. NF-kappaB is the critical factor involved in the upregulation of EMMPRIN induced by angII.

Role of TRPC1 and NF-kappaB in mediating angiotensin II-induced Ca2+ entry and endothelial hyperpermeability.

Endothelial dysfunction is associated with cardiovascular diseases. The Ca(2+) influx occurring via activation of plasmalemma Ca(2+) channels was shown to be critical in signaling the increase in endothelial permeability in response to a variety of permeability-increasing mediators. It has been reported that angiotensin II (AngII) could induce Ca(2+) signaling in some cells, and transient receptor potential canonical 1 (TRPC1) had an important role in this process. The objective of this study was to examine the mechanism of AngII-induced Ca(2+) entry and vascular endothelial hyperpermeability. Human umbilical vein endothelial cells (HUVECs) exposed to AngII exhibited dose-dependent increase in [Ca(2+)]i and endothelial permeability. Quantitative real-time RT-PCR and Western blotting showed that the level of TRPC1 expression had increased significantly at 12h and at 24h after treatment of HUEVCs with AngII. The expression of p65 was suppressed using an RNAi strategy. The results showed that the NF-kappaB signaling pathway and type-1 receptor of AngII was involved in AngII-induced TRPC1 upregulation. Moreover, knockdown of TRPC1 and NF-kappaB expression attenuates AngII-induced [Ca(2+)]i and endothelial permeability. NF-kappaB and TRPC1 have critical roles in AngII-induced Ca(2+) entry and endothelial permeability.

[Angiotensin II up-regulates expression of inducible nitric oxide synthase in human umbilical endothelial cells: roles of AT1 and AT2].

OBJECTIVE: Angiotensin II is an important pro inflammation factor in the cardiovascular system. This experiment is aimed to study the effects of angiotensin II on inducible nitric oxide synthase expression in human umbilical endothelial cells. METHODS: Human umbilical endothelial cells were cultured in vitro and treated with angiotensin II alone or in combination with AT1, AT2 and NF-kappaB inhibitors respectively. The inducible nitric oxide synthase expressions at protein and mRNA levels were measured with Western blot and reverse transcription-polymerase chain reaction (RT-PCR), and the activity of NF-kappaB was analyzed with EMSA. RESULTS: Angiotensin II up-regulated inducible nitric oxide synthase expressions at the protein and mRNA levels at 5 h (P < 0.05), the activity of NF-kappaB was enhanced at 2 h (P < 0.05). These effects could be blocked by AT1 and NF-kappaB inhibitors but not by AT2 inhibitor. CONCLUSION: Angiotensin II can upregulate the expression of inducible nitric oxide synthase through NF-kappaB pathway in human umbilical endothelial cells. AT1, other than AT2, play a key role in this process.

[Changes of mitochondrial genes expressed in the brain tissue of rat in stroke-like episodes rats].

OBJECTIVE: Stroke is a complex disorder caused by a combination of genetic and environmental factors. Epidemiological studies have provided evidence of genetic influence on the development of human stroke. However, genetic changes which contribute to the development of stroke are not well known. This study was designed to gain a deep insight into that aspect. METHODS: Using cold-stimuli plus high-salt intake as environmental risk factors, the authors established a hypertension model in rats, which produced a complication of stroke. Then, they used the suppression subtractive hybridization(SSH) technique to identify the differential genes that specifically expressed in total cerebrum tissue of the rats in stroke group. A comparison was made between two populations, namely the control group and stroke group. RESULTS: By the use of SSH approach, a total of 576 clones were generated in this study from two subtractive libraries, among them 456 clones were usable and were analyzed. Genes for metabolism transcripts in stroke group were shown to be up-regulated (P<0.01). Mitochondrial transcripts were observed in a high rate of 26.5%. CONCLUSION: The findings suggested that mitochondrial genes should induce an increased sensitivity to stroke through the changes of gene expressions. Mitochondrial genes probably play important roles in the causes and effects of stroke.

[Tumor necrosis factor alpha and myocardial matrix metalloproteinases in left ventricular remodeling].

OBJECTIVE: The cytokine tumor necrosis factor (TNF) alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. It is essential to study the changes of plasma levels of TNF alpha and matrix metalloproteinase-2,3,9 (MMP-2,3,9) expressions in myocardium during congestive heart failure (CHF). METHODS: Plasma levels of TNF alpha were measured with enzyme-linked immunoassay in CHF patients of various degrees and in healthy controls. Using Western blotting assay, we detected the protein expressions of MMP-2,3,9 on myocardial tissue in CHF patients and in healthy controls. Cardiac function parameters were measured with echocardiographic studies. RESULTS: Plasma levels of TNF alpha increased significantly in patients with CHF (P < 0.05 or < 0.01). The protein expressions of MMP-2,3,9 were significantly higher in patients with CHF than in controls (P < 0.05 or < 0.01). The higher the degree of CHF, the greater the numbers of expressions. No changes of MMP-2 could be found between the controls and CHF patients of NYHA II. There was a positive correlation between plasma levels of TNF alpha and the protein expressions of MMP-2,3,9 (P < 0.01 or < 0.001). CONCLUSIONS: It is suggested that alterations of TNF alpha may stimulate the expressions of MMPs, contribute to myocardial remodeling and lead to the development and progression of congestive heart failure. These changes may induce a direct effect on the progression and deterioration of heart failure.