Atherosclerosis最新文献

Background and aims: Patients with homozygous familial hypercholesterolemia (HoFH) respond to standard lipid lowering therapy (LLT) poorly due to biallelic abnormalities affecting low-density lipoprotein receptor (LDLR) function. Relatively little information stratified by functional genotyping is available.

Methods: We evaluated lowering of low-density lipoprotein cholesterol (LDL-C) with statins, statins plus ezetimibe or add-on proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in 175 patients with HoFH according to LDLR functional genotyping (defective/defective = 119, defective/null = 38, null/null = 18).

Results: LLT resulted in significant LDL-C percent reductions in all 3 subgroups ranging from 17 ± 19 % (mean ± SD) in the null/null subgroup to 29 ± 21 % in the defective/defective subgroup. Achievement of ≥50 % LDL-C reduction was not seen in the null/null subgroup. Achievement of this plus LDL-C < 2.6 mmol/L was seen only in the defective/defective subgroup but rarely (2.5 %, 3/119 patients). While responses to statin plus ezetimibe and add-on PCSK9 inhibitors were progressively and significantly attenuated in the defective/null and null/null subgroups, there was no difference according to functional genotyping in the response to statins. All 3 subgroups showed mean LDL-C lowering in the range of 25-29 % in response to statins.

Conclusions: LDLR-dependent LLT achieves significant LDL-C lowering in patients with HoFH which is modulated by functional genotyping except in the case of statins, possibly because of potential non-LDLR-dependent mechanisms of action. However, optimization of LDL-C remains rare and underscores the need for accessible and non-LDLR-dependent LDL-C lowering therapies.

Background: Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and ferroptosis remain unclear. This study investigated the regulatory function of C-C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and ferroptosis.

Methods: Bioinformatics analysis and single-cell RNA sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. Apoe^-/- mice were induced by a high-fat diet in vivo. Calcification, oxidative stress, and ferroptosis markers were assessed by pathological staining, enzyme-linked immunosorbent assay, and Western blot, respectively. Ferroptosis was modulated using Ferrostatin-1 (inhibitor) or Erastin (inducer), and chemokine signaling was activated with the CXC motif chemokine receptor 4 (CXCR4) agonist ATI-2341 TFA.

Results: CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in Apoe^-/- mice. Ferroptosis inhibition mirrored these effects, while its induction reversed CCL5-knockdown benefits. Furthermore, chemokine signaling pathway was screened as the downstream pathway of CCL5. Mechanistically, CCL5 knockdown suppressed CXCR4/CXCL12 expression. Activating chemokine signaling with TFA abolished the protective effects of CCL5 silencing on calcification, ferroptosis, and oxidative stress in vitro and in vivo.

Conclusion: CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD.