Aortic ER Stress in Streptozotocin-Induced Diabetes Mellitus in APA Hamsters

Abstract

Abstract:Atherosclerosis is thought to be associated with endoplasmic reticulum (ER) dysfunction and the accumulation of unfolded proteins. In this study, we examined the relationship between atherosclerosis and ER stress and the effect of sodium 4-phenylbutyrate (4-PBA), a kind of chemical chaperone, on atherosclerosis in streptozotocin-induced diabetic APA hamsters. Male, 8-week-old, APA hamsters were injected with streptozotocin (30 mg/ kg body weight) to induce diabetes mellitus, and ER stress was evaluated immunohistochemically or by semi-quantitative RT-PCR analysis using ER stress markers such as calreticulin and GPR78. Control hamsters were injected with citrate buffer and were similarly analyzed. In the aorta of control animals, a weak ER stress was detected, and 4-PBA treatment decreased the calreticulin-and GRP78-positive areas and also reduced the mRNA levels of calreticulin and GRP78. On the other hand, strong ER stress was detected at the lesser curvature of the aortic arch of streptozotocin-induced diabetic APA hamsters. However, 4-PBA treatment failed to lessen the ER stress in the aorta and had no effect on improvement of the atherosclerotic lesions. These results may provide an explanation for the complex etiology of atherosclerosis accompanied by diabetes mellitus and various other clinical phenotypes of atherosclerosis.

Calreticulin Regulates Transforming Growth Factor-β-stimulated Extracellular Matrix Production

“…CRT expression is increased in a number of different fibrotic tissues, including lung, kidney, and diabetic atherosclerotic vasculature (2, 4), 4 suggesting an involvement in fibrotic processes. CRT acts as a collagen chaperone to mediate collagen ER-Golgi trafficking, processing, and incorporation into the ECM (24).…”

“…In the lung, ER stress-induced alveolar epithelial cell apoptosis is thought to be a significant factor in the development of fibrosis (1,6,15). However, ER stress is also associated with fibroproliferative remodeling in tissues such as the diabetic vasculature where apoptosis is not a significant initiating factor (3,4). This suggests that ER stress can drive pathways that promote fibrosis through additional mechanisms.…”

“…CRT regulation of fibronectin is also thought to involve ER Ca 2ϩ (25,26). Interestingly, CRT expression is increased in multiple models of fibrosis including bleomycin-induced pulmonary fibrosis, the UUO (unilateral ureteral obstruction) model of renal fibrosis, and in chronic diseases of fibroproliferative remodeling, such as atherosclerosis (2)(3)(4). Cardiac-specific overexpression of CRT during development results in interstitial fibrosis, although the mechanisms have not been defined (27).…”

“…Chronic stimuli such as high glucose, glucosamine, or oxidative stress can up-regulate ER stress proteins and are associated with enhanced matrix production and fibrotic disease (3-5, 80, 81). Chemical chaperones such as 4-phenylbutyric reduce the expression of ER stress proteins such as CRT and GRP78 and also reduce fibrotic remodeling due to high glucose in animal models of atherosclerosis and nephropathy (3)(4)(5). Despite the growing appreciation for a role for ER stress in fibrotic disease, knowledge regarding the mechanisms by which ER stress regulates fibrosis is limited (8,15).…”

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

“…In an animal model of spontaneously developing diabetes, 4-PBA was able to normalize end-diastolic elastance, helping to alleviate a common comorbidity of diabetes (Takada et al, 2012). In contrast, 4-PBA administration did not reduce aortic ER stress nor atherosclerotic lesions in a streptozotocin-induced diabetes model (Kurokawa et al, 2009). However, 4-PBA was able to prevent streptozotocininduced diabetic nephropathy, with reduced kidney hypertrophy, reduced glomerular mesangial cell proliferation, alleviated mesangial matrix accumulation, and decreased hydroxyproline levels (Luo et al, 2010).…”