Urocortin2 attenuates diabetic coronary microvascular dysfunction by regulating macrophage extracellular vesicles

Chao Zhu, Lihua Pan, Feier Zhou, Rongchen Mao, Yali Hong, Rong Wan, Xu Li, Lai Jin, Huayiyang Zou, Hao Zhang, Qin M. Chen, Shengnan Li

Research output: Contribution to journalArticlepeer-review


Diabetic patients develop coronary microvascular dysfunction (CMD) and exhibit high mortality of coronary artery disease. Methylglyoxal (MGO) largely accumulates in the circulation due to diabetes. We addressed whether macrophages exposed to MGO exhibited damaging effect on the coronary artery and whether urocortin2 (UCN2) serve as protecting factors against such diabetes-associated complication. Type 2 diabetes was induced by high-fat diet and a single low-dose streptozotocin in mice. Small extracellular vesicles (sEV) derived from MGO-treated macrophages (MGO-sEV) were used to produce diabetes-like CMD. UCN2 was examined for a protective role against CMD. The involvement of arginase1 and IL-33 was tested by pharmacological inhibitor and IL-33-/- mice. MGO-sEV was capable of causing coronary artery endothelial dysfunction similar to that by diabetes. Immunocytochemistry studies of diabetic coronary arteries supported the transfer of arginase1 from macrophages to endothelial cells. Mechanism studies revealed arginase1 contributed to the impaired endothelium-dependent relaxation of coronary arteries in diabetic and MGO-sEV-treated mice. UCN2 significantly improved coronary artery endothelial function, and prevented MGO elevation in diabetic mice or enrichment of arginase1 in MGO-sEV. Diabetes caused a reduction of IL-33, which was also reversed by UCN2. IL-33-/- mice showed impaired endothelium-dependent relaxation of coronary arteries, which can be mitigated by arginase1 inhibition but can't be improved by UCN2 anymore, indicating the importance of restoring IL-33 for the protection against diabetic CMD by UCN2. Our data suggest that MGO-sEV induces CMD via shuttling arginase1 to coronary arteries. UCN2 is able to protect against diabetic CMD via modulating MGO-altered macrophage sEV cargoes.

Original languageEnglish (US)
Article number115976
JournalBiochemical Pharmacology
StatePublished - Jan 2024


  • Coronary microvascular dysfunction
  • Diabetes
  • Endothelium
  • Macrophage
  • Small extracellular vesicles
  • UCN2

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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