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<p>Renin-angiotensin system (RAS) activation in heart failure (HF) increases circulating angiotensin II (AII). This increases blood pressure (BP) and promotes adverse ventricular remodeling that makes HF worse. Although human HF increases with age and differs between the sexes, preclinical studies have used young, mostly male animals. We investigated sex differences in AII-induced cardiac remodeling in aging C57BL/6 mice. Mice (≈16&#xa0;months) were infused with AII (3&#xa0;mg/kg/day; 6&#xa0;weeks; osmotic minipumps). BP (tail cuff), ventricular structure/function (echocardiography), M1 (Cd80/Mcp-1/Cd68), and M2 (Mrc1) macrophage markers and profibrotic markers (transforming growth factor beta (Tgfb1), collagen 1 (Col1a1), collagen 3 (Col3a1); qPCR/Western blot) were measured. AII treatment increased BP and heart weight/tibia length in both sexes. Interestingly, AII increased wall thickness in females but reduced it and caused left ventricular (LV) dilation in males only. AII increased E/A ratios in males and isovolumic relaxation time in both sexes, indicative of diastolic dysfunction. However, isovolumic contraction time (IVCT) increased (12.0 ± 0.7 vs. 24.3 ± 3.0&#xa0;ms; <i>p</i> = 0.0001) and ejection fraction (EF) declined in males (68.9 ± 1.9 vs. 46.1 ± 4.5; <i>p</i> = 0.0001), which indicates marked systolic dysfunction. By contrast, IVCT was unaffected, and EF declined but remained well above 50% in females (68.1 ± 1.3 vs. 55.9 ± 2.0; <i>p</i> = 0.01). mRNA for macrophage markers (Cd80, Mrc1), Tgfb1, Col1a1, and Col3a1, plus collagen 1 protein increased in treated male ventricles. By contrast, AII increased collagen 3 protein in females compared to treated males. Thus, AII promotes inflammatory/profibrotic signaling, which contributes to fibrosis and impairs systolic function in aging males. Older females appear resistant to these effects.</p> Graphical Abstract <p></p>

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Angiotensin II induces sex-specific ventricular remodeling in aging C57Bl/6 mice

  • 期刊论文

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  • 发表日期：

    2025年11月7日

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  • Ninh Khuong,
  • Manish Mishra,
  • Shubham Banga,
  • Susan E. Howlett

摘要

Renin-angiotensin system (RAS) activation in heart failure (HF) increases circulating angiotensin II (AII). This increases blood pressure (BP) and promotes adverse ventricular remodeling that makes HF worse. Although human HF increases with age and differs between the sexes, preclinical studies have used young, mostly male animals. We investigated sex differences in AII-induced cardiac remodeling in aging C57BL/6 mice. Mice (≈16 months) were infused with AII (3 mg/kg/day; 6 weeks; osmotic minipumps). BP (tail cuff), ventricular structure/function (echocardiography), M1 (Cd80/Mcp-1/Cd68), and M2 (Mrc1) macrophage markers and profibrotic markers (transforming growth factor beta (Tgfb1), collagen 1 (Col1a1), collagen 3 (Col3a1); qPCR/Western blot) were measured. AII treatment increased BP and heart weight/tibia length in both sexes. Interestingly, AII increased wall thickness in females but reduced it and caused left ventricular (LV) dilation in males only. AII increased E/A ratios in males and isovolumic relaxation time in both sexes, indicative of diastolic dysfunction. However, isovolumic contraction time (IVCT) increased (12.0 ± 0.7 vs. 24.3 ± 3.0 ms; p = 0.0001) and ejection fraction (EF) declined in males (68.9 ± 1.9 vs. 46.1 ± 4.5; p = 0.0001), which indicates marked systolic dysfunction. By contrast, IVCT was unaffected, and EF declined but remained well above 50% in females (68.1 ± 1.3 vs. 55.9 ± 2.0; p = 0.01). mRNA for macrophage markers (Cd80, Mrc1), Tgfb1, Col1a1, and Col3a1, plus collagen 1 protein increased in treated male ventricles. By contrast, AII increased collagen 3 protein in females compared to treated males. Thus, AII promotes inflammatory/profibrotic signaling, which contributes to fibrosis and impairs systolic function in aging males. Older females appear resistant to these effects.

Graphical Abstract