Increased Expression of TGF-\(\beta\)1 by 4-hexylInscrinol Is Mediated by Endoplasmic Reticulum and Mitochondrial Stress in Human Umbilical Endothelial Vein Cells  
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Hallym University Kangnam Sacced Heart Hospital, Hallym University Medical Center, 1, Singil-ro, Yeongdeungpo-gu, Seoul 07441, Korea; [EMAIL_ADDRESS]  
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Thus, chemical chaperones have two conflicting aspects: one protects them from environmental stress [2], while the other kills actively proliferating competitors to save the available energy resources [3]. Translating the activity of a chemical chaperone from a microorganism to multi-cellular life, such as mammals, is a logical leap, and many variables should be considered. However, the application of chemical chaperones may have therapeutic benefits. Application of some phenolic compounds having chaperone-like properties induces apoptosis or differentiates cancer cells [4; 5]. Endoplasmic reticulum (ER) and mitochondria are the main intracellular organelles that control this response [6; 7]. Chemical chaperones may stimulate ER and mitochondrial production of proteins inducing cellular differentiation or apoptosis. If resorcinolic lipids are used in a controlled manner, their administration may differentiate cells via ER and mitochondrial stress, which could be helpful for wound healing. 4-Hexylresorcinol (4 HR) is a resorcinolic lipid and has been studied for angiogenesis and wound healing [ref]. In our previous study, application of 4 HR on human umbilical vein endothelial cells (HUVECs) increased vascular endothelial growth factor (VEGF) via the hypoxia-inducible factor (HIF)-independent pathway [8]. 4 HR-induced apoptotic stress increased the expression of transforming growth factor-\(\beta\)1 (TGF-\(\beta\)1) [9]. Treatment of TGF-\(\beta\)1 siRNA decreased VEGF expression in HUVECs, and TGF-\(\beta\)1-mediated angiogenesis increased capillary formation in a diabetic animal model [9]. The application of TGF-\(\beta\)1 supplemented with VEGF resulted in early wound closure and improved angiogenesis and vasculogenesis [10]. The application of TGF-\(\beta\)1 on stem cells induced cellular differentiation into functional pericyte-like cells [11]. However, the mechanism of 4 HR-induced TGF-\(\beta\)1 is unclear. Cellular stress is mainly transmitted to mitochondria and ER, inducing physiological or pathological events [7]. Stressed mitochondria and ER perform important functions in cellular differentiation and apoptosis [7]. If mitochondria and the ER fail to maintain cellular homeostasis, apoptosis can be activated. A successful adaptive response may introduce cellular growth and differentiation. As ER stress increases the expression level of TGF-\(\beta\)1 [12], an elevated level of TGF-\(\beta\)1 after 4 HR administration may be induced by ER stress. Tauroursodeoxycholate (TUDCA) has been used as an ER stress reliever [13]. If 4 HR increases TGF-\(\beta\)1 expression via an ER stress-mediated pathway, the application of TUDCA will alleviate TGF-\(\beta\)1 expression after 4 HR administration. Accordingly, the association between 4 HR administration and ER stress can be evaluated by investigating the change in TGF-\(\beta\)1 expression with or without TUDCA addition. Many proteins are involved in the adaptive response of the ER. Sirtuins (SIRTs) are class III histone deacetylases (HDACs) and have seven distinct isoforms (SIRT1-7) [14]. SIRTs are mainly localized in the nucleus and mitochondria [15]. The expression level of SIRTs increases in response to cellular stress [15]. SIRTs help cells to maintain cellular homeostasis in stressful situations [12; 15]. 4 HR induced several antioxidant proteins in RAW 264.7 cells [16] and HUVECs [17] and has similar antioxidant activity to resveratrol in HUVECs [8] and lymphocytes [18]. As SIRTs induce antioxidant enzymes, 4 HR may have a role as an SIRT activator. These responses may be associated with reducing mitochondrial and ER stress.