Abstract
Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after a vascular injury is a key event in developing neointimal hyperplasia. To maintain vascular function, proliferation and apoptosis of VSMCs is tightly controlled during vascular remodeling. NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) system, a key component of the oxidative stress response that acts in maintaining homeostasis, plays an important role in neointimal hyperplasia after a vascular injury; however, the role of Nrf2/Keap1 in VSMC apoptosis has not been clarified. Here we report that 14 days after arterial injury in mice, TUNEL-positive VSMCs are detected in both the neointimal and medial layers. These layers contain cells expressing high levels of Nrf2 but low Keap1 expression. In VSMCs, Keap1 depletion induces features of apoptosis, such as positive TUNEL staining and annexin V binding. These changes are associated with an increased expression of nuclear Nrf2. Simultaneous Nrf2 depletion inhibits Keap1 depletion-induced apoptosis. At 14 days after the vascular injury, Nrf2-deficient mice demonstrated fewer TUNEL-positive cells and increased neointimal formation in the neointimal and medial areas. The results suggest that the Nrf2/Keap1 system regulates VSMC apoptosis during neointimal formation, thereby inhibiting neointimal hyperplasia after a vascular injury.
Highlights
Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after a vascular injury is a key event in developing neointimal hyperplasia
In nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient(−/−) mice, fewer transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells are observed in the neointimal and medial layers, and increased neointimal formation is observed after the vascular injury. These findings suggest that the Nrf2/Keap[1] system regulates Vascular smooth muscle cells (VSMCs) apoptosis during vascular remodeling, thereby counterbalancing the effects of proliferation, which may reduce neointimal hyperplasia after a vascular injury
To examine the distribution of apoptotic cells and Nrf[2] expression in the middle stages of neointimal expansion (VSMC proliferative phase) after the vascular injury in vivo, we injured the femoral arteries of mice and performed TUNEL analysis and immunofluorescence staining with antibodies against Nrf[2] or αSMA, a VSMC marker
Summary
Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after a vascular injury is a key event in developing neointimal hyperplasia. Excessive and/or persistent stimulation of VSMCs by ROS inflicts oxidative stress and can alter the functions of VSMCs, enhance proliferation and migration, and induce resistance to apoptosis. These changes can contribute to the development of cardiovascular diseases, including arteriosclerosis and myocardial hypertrophy[8,9]. Nrf[2] gene-depletion increases neointimal formation in response to transluminal mechanical injury of the femoral artery in a mouse model of arteriosclerosis[15] These reports indicate that Nrf[2] functions as a key regulator of vascular homeostasis and protects against arteriosclerosis and subsequent vascular occlusive diseases. The direct involvement of Nrf[2] in VSMC apoptosis during physiological vascular remodeling after injury has not yet been demonstrated
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