Mechanosensitive Stem-Cell Genes and Klotho in Atherosclerotic Aortas: Regulating Spatially Deranged Expression Patterns Using Colchicine Regimens.

Abstract

Inflammatory dysregulation of mechanosensitive developmental genes may be central to atherogenesis. In the present seven-week model, we utilized colchicine regimens to curtail aortic atherogenesis in New Zealand White rabbits. We also explored the effect of colchicine regimens on atheroprotective (<i>Klotho</i>, <i>HOXA5</i>, <i>NOTCH1</i>, and <i>OCT4</i>) and proatherogenic (<i>HIF1a</i>, <i>SOX2</i>, <i>BMP4</i>, and <i>NANOG</i>) genes. The control (n = 6) and group A (n = 6) received standard and cholesterol-enriched chow, respectively. Groups B (n = 8) and C (n = 8) were fed hypercholesterolemic diet and were treated with colchicine plus fenofibrate or N-acetylcysteine (NAC), respectively. Group A developed significantly greater thoracic and abdominal aortic atherosclerosis compared to groups B (<i>p</i> &lt; 0.001) and C (<i>p</i> &lt; 0.001). Combining colchicine with NAC resulted in stronger atheroprotection both in the thoracic and the abdominal aorta. In group A thoracic aortas, <i>Klotho</i> was downregulated compared to controls (95% CI: 1.82-15.76). Both colchicine regimens upregulated <i>Klotho</i> back to baseline levels (<i>p</i> &lt; 0.001). Colchicine/fenofibrate also significantly upregulated thoracic <i>NOTCH1</i> compared to controls (95% CI: -8.09 to -0.48). Colchicine/NAC significantly reduced thoracic <i>NANOG</i> expression compared to hyperlipidemic diet alone (95% CI: 0.37-8.29). In the abdominal aorta, hypercholesterolemic diet resulted in significant downregulation of <i>HOXA5</i> (95% CI: 0.03-2.74) which was reversed with colchicine/NAC back to baseline (95% CI: -1.19 to 1.51). Colchicine/fenofibrate downregulated <i>HIF1a</i> compared to baseline (95% CI: 0.83-6.44). No significant differences were noted in terms of <i>BMP4</i>, <i>SOX2</i>, and <i>OCT4</i>. Overall, the aortic expression pattern of mechanosensitive genes seems to be spatially influenced by a hyperlipidemic diet and can be modified using colchicine-based therapy.