A GLP-1 receptor agonist semaglutide attenuates cardiac microvascular injury in HFD/STZ-induced diabetic mice

Dec 4, 2025European journal of pharmacology

Semaglutide reduces small heart blood vessel damage in diabetic mice

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Abstract

Semaglutide treatment for 8 weeks reversed disrupted cardiac microvascular structure and increased microvascular density in diabetic mice.

Diabetic mice exhibited significant cardiac microvascular injury characterized by reduced microvascular density.
Semaglutide treatment decreased advanced glycation end products and their receptors.
The treatment activated the Nrf2/HO-1/NQO1 pathway, which is associated with cellular protection.
Semaglutide inhibited the MCP-1/CCR2a/NF-κB pathway linked to inflammation.
Lower levels of inflammatory cytokines and reduced apoptosis were observed with semaglutide treatment.

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BACKGROUND: Cardiac microvascular injury from hyperlipidaemia and hyperglycaemia is associated with increased major adverse cardiovascular events (MACE). Semaglutide, a long-acting GLP-1 receptor agonist, reduces diabetic cardiovascular complications beyond its glycaemic and weight-lowering effects. However, the impact of semaglutide on diabetes-induced coronary microvascular injury and the integrated mechanisms involved remain unclear.

METHODS: A combined streptozotocin (STZ) and high-fat diet (HFD) induced diabetes model was established in ApoEmice, followed by 8 weeks of semaglutide treatment. Microvascular morphology in myocardial tissue was assessed by scanning electron microscopy, and CD31 expression was evaluated using immunofluorescence. Key pathways related to oxidative stress, inflammation, and apoptosis were examined by TUNEL staining, western blotting (WB), and reverse-transcription quantitative real-time PCR (RT-qPCR). -/-

RESULT: Diabetic mice showed disrupted cardiac microvascular structure and reduced microvascular density. Semaglutide attenuated or reversed these changes. It reduced advanced glycation end products (AGEs) and their receptors, activated the Nrf2/HO-1/NQO1 pathway, inhibited the MCP-1/CCR2a/NF-κB pathway, lowered inflammatory cytokines, and reduced apoptosis, exerting a protective effect on the cardiac microvascular system.

CONCLUSIONS: Early and sustained semaglutide treatment mitigates diabetes-related cardiac microvascular injury via multiple mechanisms, including preserving microvascular structure and density, inhibiting perivascular fibrosis, and attenuating inflammation, oxidative stress, and apoptosis.

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A GLP-1 receptor agonist semaglutide attenuates cardiac microvascular injury in HFD/STZ-induced diabetic mice

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