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<p>The phenotypic modulation of vascular smooth muscle cells (VSMCs) is a key factor in the development and progression of atherosclerosis. Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown efficacy in reducing atherosclerotic lesions; however, its specific effects on VSMC phenotype expression and the underlying intracellular signaling remain poorly understood. This study utilized VSMCs from rat aortic explants to evaluate the impact of canagliflozin on cell outgrowth, migration, cellular morphology, expression of phenotypic markers, and intracellular signaling. Canagliflozin significantly inhibited VSMC outgrowth and migration in a dose-dependent manner. Additionally, it induced an elongated VSMC morphology consistent with a contractile phenotype, while increasing the expression of contractile markers such as myocardin and calponin and reducing the expression of synthetic markers, including collagen I and III. Western blot study revealed that canagliflozin upregulated PTEN expression and suppressed AKT activation, both critical regulators of VSMC phenotype. Notably, PTEN knockdown via RNA interference reversed the inhibitory effects of canagliflozin on VSMC migration and phenotype switching, underscoring the central role of PTEN in these processes. These findings suggest that canagliflozin promotes a contractile phenotype in VSMCs by modulating the expression of phenotypic markers, upregulating PTEN, and downregulating AKT activation, thereby potentially inhibiting VSMC migration.</p>

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Canagliflozin-driven cellular re-differentiation and migration inhibition in vascular smooth muscle cells via PTEN upregulation

  • 期刊论文

  • 发表日期：

    2025年4月30日

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  • Ming-Jer Hsieh,
  • Dong-Yi Chen,
  • Cheng-Hung Lee,
  • Yu-Cih Liao,
  • Miao‐Sui Lin,
  • Jong-Hwei S. Pang

摘要

The phenotypic modulation of vascular smooth muscle cells (VSMCs) is a key factor in the development and progression of atherosclerosis. Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown efficacy in reducing atherosclerotic lesions; however, its specific effects on VSMC phenotype expression and the underlying intracellular signaling remain poorly understood. This study utilized VSMCs from rat aortic explants to evaluate the impact of canagliflozin on cell outgrowth, migration, cellular morphology, expression of phenotypic markers, and intracellular signaling. Canagliflozin significantly inhibited VSMC outgrowth and migration in a dose-dependent manner. Additionally, it induced an elongated VSMC morphology consistent with a contractile phenotype, while increasing the expression of contractile markers such as myocardin and calponin and reducing the expression of synthetic markers, including collagen I and III. Western blot study revealed that canagliflozin upregulated PTEN expression and suppressed AKT activation, both critical regulators of VSMC phenotype. Notably, PTEN knockdown via RNA interference reversed the inhibitory effects of canagliflozin on VSMC migration and phenotype switching, underscoring the central role of PTEN in these processes. These findings suggest that canagliflozin promotes a contractile phenotype in VSMCs by modulating the expression of phenotypic markers, upregulating PTEN, and downregulating AKT activation, thereby potentially inhibiting VSMC migration.