HOXA1 participates in VSMC-to-macrophage-like cell transformation via regulation of NF-& kappa;B p65 and KLF4: a potential mechanism of atherosclerosis pathogenesis

BackgroundMacrophage-like transformation of vascular smooth muscle cells (VSMCs) is a risk factor of atherosclerosis (AS) progression. Transcription factor homeobox A1 (HOXA1) plays functional roles in differentiation and development. This study aims to explore the role of HOXA1 in VSMC transformation, thereby providing evidence for the potential mechanism of AS pathogenesis.MethodsHigh fat diet (HFD)-fed apolipoprotein E knockout (ApoE(-/-)) mice were applied as an in vivo model to imitate AS, while 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POV-PC)-treated VSMCs were applied as an in vitro model. Recombinant adeno-associated-virus-1 (AAV-1) vectors that express short-hairpin RNAs targeting HOXA1, herein referred as AAV1-shHOXA1, were generated for the loss-of-function experiments throughout the study.ResultsIn the aortic root of AS mice, lipid deposition was severer and HOXA1 expression was higher than the wide-type mice fed with normal diet or HFD. Silencing of HOXA1 inhibited the AS-induced weight gain, inflammatory response, serum and liver lipid metabolism disorder and atherosclerotic plaque formation. Besides, lesions from AS mice with HOXA1 knockdown showed less trans-differentiation of VSMCs to macrophage-like cells, along with a suppression of kruppel-like factor 4 (KLF4) and nuclear factor (NF)-& kappa;B RelA (p65) expression. In vitro experiments consistently confirmed that HOXA1 knockdown suppressed lipid accumulation, VSMC-to-macrophage phenotypic switch and inflammation in POV-PC-treated VSMCs. Mechanism investigations further illustrated that HOXA1 transcriptionally activated RelA and KLF4 to participate in the pathological manifestations of VSMCs.ConclusionsHOXA1 participates in AS progression by regulating VSMCs plasticity via regulation of NF-& kappa;B p65 and KLF4. HOXA1 has the potential to be a biomarker or therapeutic target for AS.

Automated summary

HOXA1 plays a significant role in the transformation of vascular smooth muscle cells (VSMCs) and may be involved in the pathogenesis of atherosclerosis (AS). Inhibition of HOXA1 can alleviate weight gain, inflammatory response, lipid metabolism disorder, and atherosclerotic plaque formation in AS mice. Furthermore, HOXA1 knockdown suppresses the VSMC-to-macrophage phenotypic switch and inflammation in POV-PC-treated VSMCs by regulating NF-κB p65 and KLF4.