| First Author | Wu Y | Year | 2022 |
| Journal | Biomed Pharmacother | Volume | 151 |
| Pages | 113172 | PubMed ID | 35644115 |
| Mgi Jnum | J:327507 | Mgi Id | MGI:7311256 |
| Doi | 10.1016/j.biopha.2022.113172 | Citation | Wu Y, et al. (2022) Endothelium-targeted delivery of PPARdelta by adeno-associated virus serotype 1 ameliorates vascular injury induced by hindlimb ischemia in obese mice. Biomed Pharmacother 151:113172 |
| abstractText | Diabetic vasculopathy is a major health problem worldwide. Peripheral arterial disease (PAD), and in its severe form, critical limb ischemia is a major form of diabetic vasculopathy with limited treatment options. Existing literature suggested an important role of PPARdelta in vascular homeostasis. It remains elusive for using PPARdelta as a potential therapeutic target due to mostly the side effects of PPARdelta agonists. To explore the roles of PPARdelta in endothelial homeostasis, endothelial cell (EC) selective Ppard knockout and controlled mice were subjected to hindlimb ischemia (HLI) injury. The muscle ECs were sorted for single-cell RNA sequencing (scRNA-seq) analysis. HLI was also performed in high fat diet (HFD)-induced obese mice to examine the function of PPARdelta in obese mice with delayed vascular repair. Adeno-associated virus type 1 (AAV1) carrying ICAM2 promoter to target endothelium for overexpressing PPARdelta was injected into the injured muscles of normal chow- and HFD-fed obese mice before HLI surgery was performed. scRNA-seq analysis of ECs in ischemic muscles revealed a pivotal role of PPARdelta in endothelial homeostasis. PPARdelta expression was diminished both after HLI injury, and also in obese mice, which showed further delayed vascular repair. Endothelium-targeted delivery of PPARdelta by AAV1 improved perfusion recovery, increased capillary density, restored endothelial integrity, suppressed vascular inflammation, and promoted muscle regeneration in ischemic hindlimbs of both lean and obese mice. Our study indicated the effectiveness of endothelium-targeted PPARdelta overexpression for restoring functional vasculature after ischemic injury, which might be a promising option of gene therapy to treat PAD and CLI. |
