Angiotensin II reduces glyoxalase 1 activity and expression in vascular smooth muscle cells: Implications for diabetic vascular complications.

Angiotensin II (Ang II), a key mediator of vascular diseases, is linked to methylglyoxal (MGO) formation, a by-product of glucose metabolism implicated in vascular complications. The glyoxalase system, consisting of glyoxalase 1 (Glo1) and reduced glutathione (GSH), is responsible for detoxifying MGO. This study investigated the effect of Ang II on Glo1 activity and expression in vascular smooth muscle cells (VSMCs). Primary VSMCs were isolated from rat aortas and exposed to Ang II under standard or high glucose conditions. We examined Glo1 activity, expression, intracellular GSH, and methylglyoxal-derived hydroimidazolone 1 (MG-H1) levels. We also analyzed the expressions of nuclear factor-κB (NF-κB) p65 and nuclear factor erythroid 2-related factor 2 (Nrf2) as potential regulators of Glo1 expression. The results demonstrated that Ang II reduced Glo1 activity, expression, and GSH levels while increasing MG-H1 levels in VSMCs. Telmisartan and irbesartan, AT1R blockers, restored Glo1 activity, expression, and GSH levels and alleviated MG-H1 levels. Treatment with AT1R blockers or inhibitors targeting signaling pathways involved in Ang II-induced responses mitigated these effects. High glucose exacerbated the reduction in Glo1 activity and expression. In conclusion, this study provides evidence that Ang II reduces Glo1 activity and expression in VSMCs, which may contribute to developing vascular complications in diabetes. AT1R blockers and inhibitors targeting specific signaling pathways show potential in restoring Glo1 function and mitigating MGO-associated damage. These findings highlight the complex interactions between RAS, MGO, and vascular diseases, highlighting potential therapeutic targets for diabetic vascular complications.

Time-varying causality between income inequality and ecological footprint in Turkey.

This paper investigates the relationship between income inequality and environmental degradation for the case of Turkey between 1987 and 2017 through the bootstrap causality method that changes over time. The study used the GINI coefficient to denote income inequality and ecological footprint (EFP) to represent environmental degradation. According to the analysis results, a causal relationship has been determined for Turkey from GINI to EFP between 2002 and 2015 and from EFP to GINI between 2002 and 2008. Thanks to the method used in the analysis, it was concluded that GINI-affected EFP positively between 2002 and 2005 and negatively between 2006 and 2015. Between 2002 and 2005, Turkey endured a difficult period of restructuring after two major banking crises in 1999 and 2001. The rapid development, especially in industry and urbanization, caused environmental degradation in this period. Between 2006 and 2015, the central dynamic of Turkey's growth trend was the finance sector, and rapid privatizations were realized. Nevertheless, the income justice improvement in this period negatively impacted the environment due to consumption and production habits. Policymakers should evaluate Turkey in its economic reality and produce policies accordingly. Environmental awareness should be increased in the production and consumption activities of all segments of society, benefiting from the developments in income distribution. The ecological impact of the income redistribution policy, along with its market and social consequences, needs to be evaluated.

Methylglyoxal enhances the proliferation of vascular smooth muscle cells via Akt phosphorylation.

Methylglyoxal (MGO) is predominantly produced as a by-product of the glycolysis pathway. The glyoxalase system effectively removes it in a healthy organism. However, this process is impaired, and MGO level is elevated in people with diabetes. MGO's effects on proliferation were mostly studied in cancer cells, and the data in other cell types are limited. This study inspected the proliferative capacity of MGO in vascular smooth muscle cells (VSMCs), which have a crucial role in atherosclerosis and restenosis. The roles of ERK1/2 MAPK and Akt phosphorylations in proliferation were determined. Telmisartan, irbesartan, and NF-κB inhibitor JSH-23's roles in protecting the cells from MGO-induced proliferation were also investigated. Primary VSMCs were isolated from the rat aorta. The proliferation was spectrophotometrically measured by using a tetrazolium salt (Wst-1). The cells were cultured in standard media (SM, glucose conc. 5.5 mM) or high glucose media (HGM, glucose conc. 25 mM; an in vitro model of hyperglycemia). ERK1/2 MAPK and Akt phosphorylations were determined by the western blot method. MGO triggered the proliferation at 24, 48, and 72 hrs in SM and 48 and 72 hrs in HGM. Low doses of MGO such as 1-10 µM can induce proliferation. The phosphorylated ERK1/2 MAPK and Akt participated in MGO-induced proliferation. Telmisartan, irbesartan, and JSH-23 effectively alleviated the proliferation and Akt phosphorylation. MGO could proliferate VSMCs even at low doses. Moreover, hypertensive diabetic patients might benefit from a sartan family drug to protect VSMCs from MGO-induced proliferation.

Methylglyoxal stimulates endoplasmic reticulum stress in vascular smooth muscle cells.

Methylglyoxal (MGO) is considered responsible for the detrimental effects of high blood glucose. MGO is produced as a by-product of the glycolysis pathway. While the glyoxalase system removes it, the system fails in people with diabetes. MGO concentration is detected as elevated in these patients. Endoplasmic reticulum (ER) stress may play a role in atherosclerosis progression and vascular diseases. If ER stress persists, it may result in apoptosis of the cell. As a result, stabilized plaque structure by these cells may be ruptured and cause a stroke. This study aimed to investigate whether MGO can induce ER stress and apoptosis in vascular smooth muscle cells (VSMCs). Also, the effects of aminoguanidine hydrochloride (AGH), 4-phenylbutyric acid (4-PBA), and tauroursodeoxycholic acid (TUDCA) were scrutinized to relieve ER stress. VSMCs were isolated from rat aorta and cultured primary. PERK phosphorylation, IRE1α, ATF6, BiP (Grp78), and CHOP expressions were detected by the western blot technique. A caspase-3 assay kit measured the apoptosis. MGO could stimulate the main three ER stress pathways, PERK phosphorylation, IRE1α, and ATF6 expressions in a time- and concentration-dependent manner. Furthermore, AGH, 4-PBA, and TUDCA alleviated MGO-induced ER stress. However, we detected neither an increase in CHOP expression nor apoptosis in VSMCs. This study shows that MGO induces ER stress even at low concentrations in VSMCs. The impaired glyoxalase system may cause MGO accumulation and result in persisted ER stress. Supposing that ER stress is not mitigated, this table might be finalized in cell apoptosis, plaque rupture, and stroke.

Antiandrogen abiraterone and docetaxel treatments affect Notch1, Jagged1 and Hes1 expressions in metastatic prostate cancer cells.

BACKGROUND: Prostate cancer is the most common cancer in men. A Notch signaling pathway is an important pathway in cell proliferation, differentiation, and fate. However, currently, the effects of abiraterone based-anti-androgene therapy and docetaxel, the most commonly used standard chemotherapy in prostate cancer treatment, on Notch signaling pathway are unknown. This study aimed to investigate the effects of abiraterone acetate and docetaxel on the expression of Notch1, Jagged1 and Hes1 in prostate cancer cell lines. METHODS: In vitro effects of abiraterone acetate and docetaxel were examined on Notch1, Jagged1, and Hes1 expression in LNCaP and PC3 PCa cell lines by immunofluorescence, Western blot, and qRT-PCR. MTT proliferation assay was used to evaluate cell proliferation and survival. RESULTS: We found that in the treatment of PC3 cells with abiraterone acetate, docetaxel, and their combination, only mRNA expressions of Notch1, Jagged1 and Hes1 were affected compared to control, but these expression differences were not observed in protein expression. In LNCaP cells, abiraterone acetate and the combination groups reduced Notch1 protein expression. All treatment groups did not alter Jagged1 expression compared to control, but significantly increased the Hes1 gene and protein expression. CONCLUSION: Our findings suggest that abiraterone and docetaxel treatments affects the expression of Notch signal pathway proteins. But these drugs especially cause significant upregulation in Hes1 expression in PCa cells. Therefore, co-application of Notch signaling inhibitors together with docetaxel and abiraterone chemotherapy, it was thought that decreased Hes1 expression could be stopped the deterioration of the prognosis of the patient.

Is the relationship between oil-gas prices index and economic growth in Turkey permanent?

Oil and gas are the most important inputs that countries use in their production process. For this reason, changes in oil-gas prices affect economic growth, which is the most important macroeconomic performance indicator. This study aims to investigate whether the relations between the oil-gas prices index and economic growth are permanent in Turkey, covering the period 1998Q1-2019Q4. For this purpose, the relationships between variables are first examined by Granger and Toda-Yamamoto causality tests with structural breaks. Then, we analyze whether the relationships between them are permanent using frequency domain causality tests based on these two tests. There is insignificant causality relationship between the variables according to Granger and the Frequency Domain Causality Test results based on this test. However, according to the results of the Toda-Yamamoto causality test with a structural break, there is a causality relationship from oil-gas prices to economic growth. According to the results of the Frequency Domain Causality Test based on this test, the permanent effect of oil-gas prices on economic growth is approximately five years.

Losartan inhibits EGFR transactivation in vascular smooth muscle cells

Background/aim: Angiotensin II (Ang II)-induced molecular signaling pathways play a significant role in the progression of cardiovascular diseases, including hypertension and atherosclerosis. In addition to the well-known effects of Ang II, it may activate epidermal growth factor receptor (EGFR) in a process known as transactivation, which contributes to vascular pathologies. The aim of this study was to determine whether losartan could reduce EGFR transactivation induced by Ang II. Additionally, we evaluated the roles of heparin-binding epidermal-like growth factor (HB-EGF) and matrix metalloproteinases (MMPs) in Ang II-induced EGFR transactivation. Materials and methods: Vascular smooth muscle cells were isolated from a rat aorta and grown in primary culture. Ang II-induced EGFR phosphorylation (tyrosine 1068) and ERK1/2 MAPK phosphorylation (threonine 202 and tyrosine 204) were evaluated by western blotting. Results: Ang II induced EGFR phosphorylation through the Ang II type I receptor (P < 0.05). The transactivation process was inhibited by losartan and mediated by HB-EGF and MMPs. Ang II transactivates EGFR in an AT1R-dependent manner. Conclusion: The results of this study show that losartan, a widely used antihypertensive agent, can suppress EGFR phosphorylation (Y1068) upon Ang II stimulation in vascular smooth muscle cells. EGFR inhibition is a candidate therapy for combating cardiovascular diseases such as hypertension and atherosclerosis.

Effect of uric acid on inflammatory COX-2 and ROS pathways in vascular smooth muscle cells.

Hyperuricemia is thought to play a role in cardiovascular diseases (CVD), including hypertension, coronary artery disease and atherosclerosis. However, exactly how uric acid contributes to these pathologies is unknown. An underlying mechanism of inflammatory diseases, such as atherosclerosis, includes enhanced production of cyclooxygenase-2 (COX-2) and superoxide anion. Here, we aimed to examine the effect of uric acid on inflammatory COX-2 and superoxide anion production and to determine the role of losartan. Primarily cultured vascular smooth muscle cells (VSMCs) were time and dose-dependently induced by uric acid and COX-2 and superoxide anion levels were measured. COX-2 levels were determined by ELISA, and superoxide anion was measured by the superoxide dismutase (SOD)-inhibitable reduction of ferricytochrome c method. Uric acid elevated COX-2 levels in a time-dependent manner. Angiotensin-II receptor blocker, losartan, diminished uric-acid-induced COX-2 elevation. Uric acid also increased superoxide anion level in VSMCs. Uric acid plays an important role in CVD pathogenesis by inducing inflammatory COX-2 and ROS pathways. This is the first study demonstrating losartan's ability to reduce uric-acid-induced COX-2 elevation.