Histone lactylation-mediated metabolic remodeling in vascular smooth muscle cells aggravates aortic aneurysm and dissection via promoting lactate accumulation

Background

Vascular smooth muscle cells (VSMCs) undergo phenotypic changes during the development of aortic aneurysm and dissection (AAD). Metabolism shifts from oxidative phosphorylation (OXPHOS) to glycolysis. Recent studies suggested glycolysis-associated histone lactylation was involved in the regulation of cardiovascular disease, the role of histone lactylation in AAD remains unclear.

Methods

The epigenetic regulation of histone lactylation was analyzed in the aorta of patients with aortic aneurysm (AA) and in a murine model of AAD, as well as

VSMCs treated with angiotensin II (AngII). CUT&Tag assay and ChIP-qPCR were using to explored the epigenetic pathway involving H4K16 lactylation (H4K16la) in vitro and vivo. To examine the role of H4K16la in AAD formation, mice lacking Pdk1 or Kat7 in VSMCs were created. Mice were treated with pharmacological inhibitors of Pdk1 or Kat7. The level of blood lactate, aortic lactate, and aortic H4K16la were compared between AA patients and controls.

Results

Histone lactylation (H4K16la) was increased in the aortic tissues of AAD patients and mice. Enhanced histone lactylation was linked to increase in PDK1 transcription, which accelerated lactate production in VSMCs. A positive feedback loop was identified involving H4K16la, PDK1, and lactate; this pathway alters the metabolism and phenotype of VSMCs. KAT7 was found to be a histone lactyltransferase for histone lactylation in VSMCs. Genetic or pharmacological inhibition of PDK1 or KAT7 decreased AAD injury by disrupting the H4K16la/ PDK1/ lactate pathway. Patients with AAD have elevated lactate in blood and aortic tissues, as well as elevated H4K16la in aortic tissues, compared to control patients.

Conclusions

Histone lactylation changes the metabolism and phenotype of VSMC in AAD. Inhibition of PDK1 or KAT7 may be a novel approach to treat or prevent AAD.