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

Abstract

Aims: 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 (Klotho, HOXA5, NOTCH1, and OCT4) and proatherogenic (HIF1a, SOX2, BMP4, and NANOG) genes. Methods: 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. Results: Group A developed significantly greater thoracic and abdominal aortic atherosclerosis compared to groups B (p < 0.001) and C (p < 0.001). Combining colchicine with NAC resulted in stronger atheroprotection both in the thoracic and the abdominal aorta. In group A thoracic aortas, Klotho was downregulated compared to controls (95% CI: 1.82–15.76). Both colchicine regimens upregulated Klotho back to baseline levels (p < 0.001). Colchicine/fenofibrate also significantly upregulated thoracic NOTCH1 compared to controls (95% CI: −8.09 to −0.48). Colchicine/NAC significantly reduced thoracic NANOG expression compared to hyperlipidemic diet alone (95% CI: 0.37–8.29). In the abdominal aorta, hypercholesterolemic diet resulted in significant downregulation of HOXA5 (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 HIF1a compared to baseline (95% CI: 0.83–6.44). No significant differences were noted in terms of BMP4, SOX2, and OCT4. Conclusions: 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.

Myocardial Expression of Pluripotency, Longevity, and Proinflammatory Genes in the Context of Hypercholesterolemia and Statin Treatment

“…Our analysis also extended into emerging atherosclerosis markers, such as klotho and pluripotency genes [6,7,[40][41][42][43][44]. Klotho is an anti-aging hormone that plays a pivotal role in the preservation of endothelial cell integrity [45][46][47].…”

“…We recently conveyed that colchicine-based treatment can upregulate klotho levels in atherosclerotic aortic tissue [6]. While colchicine remains the sole FDA-approved immunomodulator targeting proatherogenic inflammation with effects on klotho levels (among other molecules) [55], our research presents a novel therapeutic pathway for consideration.…”

“…Alongside established biomarkers, recent studies are investigating novel atheroprotective agents such as klotho (an anti-aging hormone) and stem cell-related genes including HOXA5 and Krüppel-like factors (KLF). Additional attention is directed towards proatherogenic pluripotency factors such as NANOG and HIF1α [1,[6][7][8]. Dysregulation of their expression has been implicated in various aspects of atherogenesis, including increased release of pro-inflammatory cytokines and chemokines, upregulation of adhesion molecules, migration and phenotypic switching of vascular smooth muscle cells (VSMCs), alterations in extracellular matrix, oxidative stress, and the development of neointimal hyperplasia [6,9,10].…”

The association between the triglyceride–glucose index and the risk of cardiovascular disease in US population aged ≤ 65 years with prediabetes or diabetes: a population-based study

“…The TyG index also demonstrated superior predictive capabilities for MetS compared to HOMA-IR [ 63 ]. Moreover, a meta-analysis of 13 observational studies corroborated the TyG index's optimal sensitivity and specificity for MetS screening, suggesting its potential as a valuable alternative biomarker for clinical follow-up management in MetS populations [ 64 ]. Notably, a significant elevation in the TyG index was observed in young adults diagnosed with MetS [ 65 ].…”

Transfection of Vein Grafts with Early Growth Response Factor-1 Oligodeoxynucleotide Decoy: Effects on Stem-Cell Genes and Toll-like Receptor-Mediated Inflammation

“…Emerging evidence has also revealed that the expression of various stem cell genes (including KLF4 (Krüppel-like factor 4), HOXA5, NANOG, and HIF1α (hypoxia-inducible factor 1-alpha)) can be dysregulated by shear stress [9][10][11]. These genetic alterations may potentially orchestrate specific patterns in venous graft failure, including the development of neointimal hyperplasia [12][13][14].…”