Journal of Cardiothoracic-Renal Research最新文献

Background

Cardiac complications have been demonstrated as a major cause of morbidity and mortality in the diabetic population. However, the mechanisms underlying diabetes-induced cardiomyopathy remain unclear. We tested the hypothesis that endothelin-1 (ET-1) plays an important role in diabetes-induced pathogenesis of ventricular myocyte dysfunction.

Methods

Diabetic rat was induced by an intravenous injection of streptozotocin (STZ). The potential contribution of endothelin to diabetic cardiomyopathy was determined by chronic treatment of rats with the ET-1 receptor antagonist, bosentan. Myocyte contractility and intracellular calcium homeostasis were compared using an edge detection/micro-fluorescent system.

Results

Ventricular myocytes isolated from diabetic rats exhibited significant depression in cell contractility and altered intracellular Ca²⁺ ([Ca²⁺]_i) transient. On the other hand, L-type Ca²⁺ channel activity in diabetic myocytes was not altered. Bosentan treatment successfully prevented myocyte contractile dysfunction and [Ca²⁺]_i depression in diabetic rats without affecting myocyte function from control rats. Bosentan had no effect on Ca²⁺ channel activity in myocytes obtained from both control and diabetic rats.

Conclusion

These data demonstrate that elevated ET-1 in diabetic animals plays an important role in the diabetes-induced cardiac myocyte dysfunction. Blockade of ET-1 receptor may be a potential therapeutic strategy in the treatment of diabetes-induced heart failure.

We have recently demonstrated that a novel angiotensin II (Ang II) type 1 receptor-associated protein, GLP induces cellular hypertrophy and Ang II stimulated GLP mRNA expression in a time-, dose-, and AT₁ receptor-dependent manner in rat immortalized renal proximal tubular cells (IRPTCs). The present studies investigated which signaling pathways are involved in Ang II stimulated GLP mRNA expression in IRPTCs. Cellular GLP mRNA expression was determined by reverse transcription polymerase chain reaction. The effect of Ang II was blocked by epidermal growth factor receptor inhibitor, AG1478, PKC inhibitor, GF109203X, MAPK kinase inhibitor, PD98059, antioxidants, taurine and tiron, and NADH/NADPH oxidase inhibitor, DPI, whereas, no effects were observed on Ang II-induced GLP mRNA expression with p38 MAPK inhibitors, SB203580 and PD169316, and Janus kinase 2 inhibitor, AG490. IRPTCs stably expressing GLP gene significantly increased reactive oxygen species (ROS) generation compared to control IRPTCs analyzed by lucigenin assay. Furthermore, NADH/NADPH oxidase inhibitor, DPI, and antioxidants taurine and tiron inhibited GLP-induced total protein content and de novo protein synthesis. These studies demonstrated that the stimulatory action of Ang II on GLP mRNA expression in IRPTCs is mediated by multiple signal mechanisms, transactivation of EGF receptor and subsequent MAPK activation, PKC activation and ROS generation. Furthermore, the cellular hypertrophic effect of GLP gene in IRPTCs is mediated at least in part via ROS generation.

Graft failure in coronary artery bypass grafts (CABGs) utilizing the saphenous vein is significantly higher than in those utilizing the internal mammary artery (IMA) or the radial artery (RA). While a number of studies have described this phenomenon clinically, few have attempted to extensively examine the biological differences between vein and artery, or the short- and long-term effectiveness of their use. In addition, there is limited information on the role of reactive oxygen species (ROS) in the generation of oxidative stress in the vascular smooth muscle cell, which we speculate has a significant role in inducing apoptosis and, consequently, graft failure. The purpose of this review, thus, is to concisely describe the relationship among DNA damage, DNA repair and graft failure by examining (1) DNA lesions resulting from oxidative damage, such as 8-oxo-7,8-dihydroguanine, as well as their affiliation with human diseases, (2) biological differences in DNA damage and repair capabilities of both artery and vein, and (3) DNA repair mechanisms and the significance of several repair enzymes.