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<p>High-salt exposure is linked to maladaptive cardiac remodeling, but its underlying transcriptional mechanisms remain unclear. We investigated the effects of NaCl-supplemented high-salt/hyperosmotic stress (final Na + concentration: 190–210&#xa0;mM) on H9c2 cells. NaCl supplementation induced a distinct hypertrophic phenotype, most pronounced at 210&#xa0;mM for 48&#xa0;h, characterized by increased cell surface area, elevated protein levels of ANP and α-SMA, and upregulated mRNA expression of classic hypertrophic markers (ANP, BNP, and Myh7). Bulk RNA-seq identified 2125 differentially expressed genes under 210&#xa0;mM NaCl conditions. Functional enrichment and protein–protein interaction analyses revealed that upregulated genes were significantly enriched in extracellular matrix (ECM)-receptor interaction and PI3K/AKT signaling, suggesting potential integrin-mediated links. Experimentally, high-salt/hyperosmotic stress increased AKT phosphorylation (p-AKT), whereas pharmacological PI3K inhibition via LY294002 (5&#xa0;μM) reduced p-AKT, downregulated ANP, and attenuated cell enlargement. In conclusion, high-salt/hyperosmotic conditions drive H9c2 cell hypertrophy and transcriptomic remodeling, implicating ECM-integrin signaling and PI3K/AKT activation. These in vitro findings provide preliminary mechanistic insights into salt-induced cardiac injury, though further validation using osmotic controls and in vivo models is required.</p>

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High-salt/hyperosmotic stress induces cardiomyocyte hypertrophy via the PI3K/AKT signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Mingming Huang,
  • Zhenlin Liu,
  • Yutao Wei,
  • Xiaobo Wang,
  • Lihua Li

摘要

High-salt exposure is linked to maladaptive cardiac remodeling, but its underlying transcriptional mechanisms remain unclear. We investigated the effects of NaCl-supplemented high-salt/hyperosmotic stress (final Na + concentration: 190–210 mM) on H9c2 cells. NaCl supplementation induced a distinct hypertrophic phenotype, most pronounced at 210 mM for 48 h, characterized by increased cell surface area, elevated protein levels of ANP and α-SMA, and upregulated mRNA expression of classic hypertrophic markers (ANP, BNP, and Myh7). Bulk RNA-seq identified 2125 differentially expressed genes under 210 mM NaCl conditions. Functional enrichment and protein–protein interaction analyses revealed that upregulated genes were significantly enriched in extracellular matrix (ECM)-receptor interaction and PI3K/AKT signaling, suggesting potential integrin-mediated links. Experimentally, high-salt/hyperosmotic stress increased AKT phosphorylation (p-AKT), whereas pharmacological PI3K inhibition via LY294002 (5 μM) reduced p-AKT, downregulated ANP, and attenuated cell enlargement. In conclusion, high-salt/hyperosmotic conditions drive H9c2 cell hypertrophy and transcriptomic remodeling, implicating ECM-integrin signaling and PI3K/AKT activation. These in vitro findings provide preliminary mechanistic insights into salt-induced cardiac injury, though further validation using osmotic controls and in vivo models is required.