Anti-Proliferative Effects of Rutin on OLETF Rat Vascular Smooth Muscle Cells Stimulated by Glucose Variability
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Purpose: Proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. Rutin is a major representativeof the flavonol subclass of flavonoids and has various pharmacological activities. Currently, data are lacking regarding itseffects on VSMC proliferation induced by intermittent hyperglycemia. Here, we demonstrate the effects of rutin on VSMC proliferationand migration according to fluctuating glucose levels. Materials and Methods: Primary cultures of male Otsuka Long-Evans Tokushima Fatty (OLETF) rat VSMCs were obtained fromenzymatically dissociated rat thoracic aortas. VSMCs were incubated for 72 h with alternating normal (5.5 mmol/L) and high(25.0 mmol/L) glucose media every 12 h. Proliferation and migration of VSMCs, the proliferative molecular pathway [includingp44/42 mitogen-activated protein kinases (MAPK), mitogen-activated protein kinase kinase 1/2 (MEK1/2), p38 MAPK, phosphoinositide3-kinase (PI3K), c-Jun N-terminal protein kinase (JNK), nuclear factor kappa B (NF-κB), and Akt], the migratorypathway (big MAPK 1, BMK1), reactive oxygen species (ROS), and apoptotic pathway were analyzed. Results: We found enhanced proliferation and migration of VSMCs when cells were incubated in intermittent high glucose conditions,compared to normal glucose. These effects were lowered upon rutin treatment. Intermittent treatment with high glucosefor 72 h increased the expression of phospho-p44/42 MAPK (extracellular signal regulated kinase 1/2, ERK1/2), phospho-MEK1/2, phospho-PI3K, phospho-NF-κB, phospho-BMK1, and ROS, compared to treatment with normal glucose. These effectswere suppressed by rutin. Phospho-p38 MAPK, phospho-Akt, JNK, and apoptotic pathways [B-cell lymphoma (Bcl)-xL, Bcl-2,phospho-Bad, and caspase-3] were not affected by fluctuations in glucose levels. Conclusion: Fluctuating glucose levels increased proliferation and migration of OLETF rat VSMCs via MAPK (ERK1/2), BMK1,PI3K, and NF-κB pathways. These effects were inhibited by the antioxidant rutin.
Abstract
Purpose: Proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. Rutin is a major representativeof the flavonol subclass of flavonoids and has various pharmacological activities. Currently, data are lacking regarding itseffects on VSMC proliferation induced by intermittent hyperglycemia. Here, we demonstrate the effects of rutin on VSMC proliferationand migration according to fluctuating glucose levels. Materials and Methods: Primary cultures of male Otsuka Long-Evans Tokushima Fatty (OLETF) rat VSMCs were obtained fromenzymatically dissociated rat thoracic aortas. VSMCs were incubated for 72 h with alternating normal (5.5 mmol/L) and high(25.0 mmol/L) glucose media every 12 h. Proliferation and migration of VSMCs, the proliferative molecular pathway [includingp44/42 mitogen-activated protein kinases (MAPK), mitogen-activated protein kinase kinase 1/2 (MEK1/2), p38 MAPK, phosphoinositide3-kinase (PI3K), c-Jun N-terminal protein kinase (JNK), nuclear factor kappa B (NF-κB), and Akt], the migratorypathway (big MAPK 1, BMK1), reactive oxygen species (ROS), and apoptotic pathway were analyzed. Results: We found enhanced proliferation and migration of VSMCs when cells were incubated in intermittent high glucose conditions,compared to normal glucose. These effects were lowered upon rutin treatment. Intermittent treatment with high glucosefor 72 h increased the expression of phospho-p44/42 MAPK (extracellular signal regulated kinase 1/2, ERK1/2), phospho-MEK1/2, phospho-PI3K, phospho-NF-κB, phospho-BMK1, and ROS, compared to treatment with normal glucose. These effectswere suppressed by rutin. Phospho-p38 MAPK, phospho-Akt, JNK, and apoptotic pathways [B-cell lymphoma (Bcl)-xL, Bcl-2,phospho-Bad, and caspase-3] were not affected by fluctuations in glucose levels. Conclusion: Fluctuating glucose levels increased proliferation and migration of OLETF rat VSMCs via MAPK (ERK1/2), BMK1,PI3K, and NF-κB pathways. These effects were inhibited by the antioxidant rutin.
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