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Thoracic perivascular adipose tissue-derived PI16 alleviates vascular calcification via CKAP4/PI3K/Akt pathway
Shu Qiu1, Weixia Gao1, Dongxue Wu1
1Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Insights
Thoracic perivascular adipose tissue (tPVAT) protects against medial arterial calcification (MAC). A protein called peptidase inhibitor 16 (PI16) from tPVAT inhibits MAC by interacting with CKAP4, offering a potential therapeutic target.
Area of Science:
- Vascular Biology
- Nephrology
- Biochemistry
Background:
- Medial arterial calcification (MAC) is a serious complication of chronic kidney disease (CKD), increasing cardiovascular risk.
- Current treatments for MAC are limited, highlighting the need for new therapeutic strategies.
- The role of thoracic perivascular adipose tissue (tPVAT) in regulating vascular calcification is not well understood.
Purpose of the Study:
- To investigate the protective role of tPVAT against medial arterial calcification.
- To identify the specific mechanisms by which tPVAT influences vascular calcification.
Main Methods:
- Utilized experimental models of chronic kidney disease (CKD) and vitamin D3-induced vascular calcification.
- Employed thoracic perivascular adipose tissue (tPVAT) transplantation and in vitro studies using vascular smooth muscle cells.
- Identified key molecular factors and signaling pathways involved in the anti-calcific effects.
Main Results:
- Thoracic aortas showed delayed medial calcification compared to abdominal aortas in experimental models.
- Transplantation of tPVAT attenuated medial arterial calcification in the abdominal aorta.
- Peptidase inhibitor 16 (PI16), derived from tPVAT, was identified as a crucial anti-calcific factor.
- PI16 inhibits vascular smooth muscle cell calcification by interacting with CKAP4 and suppressing the PI3K/Akt/RUNX2 pathway.
Conclusions:
- Thoracic perivascular adipose tissue (tPVAT) exerts a protective effect against medial arterial calcification.
- Peptidase inhibitor 16 (PI16) is a key mediator of tPVAT's anti-calcific properties.
- The PI16-CKAP4 signaling pathway represents a potential therapeutic target for treating vascular calcification in chronic kidney disease.
Abstract:
Medial arterial calcification (MAC) is a major vascular complication of chronic kidney disease (CKD) and a strong predictor of cardiovascular morbidity and mortality, yet pharmacological interventions directly targeting this process remain limited. Thoracic perivascular adipose tissue (tPVAT) is increasingly recognized as a regulator of vascular homeostasis, but its role in medial arterial calcification remains unclear. Here we investigated whether tPVAT confers protection against medial arterial calcification and the underlying mechanisms. Using complementary experimental models of vascular calcification, including adenine-induced CKD and vitamin D3-induced calcification, we found that the thoracic aorta exhibited delayed medial calcification compared with the abdominal aorta. Transplantation of tPVAT attenuated abdominal aortic calcification across multiple models. A factor derived from early-stage tPVAT suppressed vascular smooth muscle cell calcification in vitro. Peptidase inhibitor 16 (PI16), predominantly derived from fibroblasts, was identified as a key anti-calcific factor in tPVAT, and its protective effect was confirmed using recombinant PI16. Mechanistically, PI16 interacted with cytoskeleton-associated protein 4 (CKAP4), a membrane-associated protein on vascular smooth muscle cells, resulting in inhibition of the PI3K/Akt/RUNX2 signaling pathway and suppression of osteogenic differentiation. These findings identify PI16 as a tPVAT-derived inhibitor of vascular calcification and reveal a PI16-CKAP4 signaling pathway that may represent a potential therapeutic target in CKD-associated vascular calcification.
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