Growth differentiation factor 15 protects against diabetic endothelial dysfunction by AMP-activated protein kinase mediation

Aims: Endothelial dysfunction is a hallmark of diabetes-associated cardiovascular complications, yet its molecular mechanisms remain incompletely elucidated. Growth Differentiation Factor 15 (GDF15) has emerged as an important modulator in metabolic and cardiovascular diseases; however, its role in diabetic endothelial dysfunction is poorly understood. This study aims to investigate the therapeutic potential of GDF15 in diabetic endothelial dysfunction and to elucidate the underlying mechanisms.

Methods: db/db mouse aortas or high glucose/high lipid (HG/HL)-treated C57BL/6 mouse aortas were exposed to GDF15 for acute or prolonged durations. Endothelium-dependent relaxation (EDR) was evaluated using wire myography. Meanwhile, western blotting was performed to assess protein levels of nuclear factor erythroid 2-related factor 2 (NRF2), NADPH Oxidase 2 (NOX2), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), total AMP-activated protein kinase (AMPK), and phosphorylated AMPK in endothelial cells treated with GDF15 in the presence or absence of HG/HL. Reactive Oxygen Species (ROS) production in en face endothelial cells of mouse aortas was measured via confocal microscopy.

Results: Exogenous GDF15 acute or prolonged administration markedly ameliorated HG/HL- and diabetes-induced endothelial dysfunction and excess Reactive Oxygen Species (ROS) generation. Meanwhile, GDF15 counteracted HG/HL-induced changes in NOX2, NRF2, ACE, and ACE2 protein expression in endothelial cells. These beneficial effects of GDF15 were mechanistically linked to AMPK upregulation, as evidenced by elevated AMPK levels in GDF15-treated endothelial cells, and the suppression of GDF15's vasoprotective effects by the AMPK Inhibitor Compound C.

Conclusions: Our findings demonstrate that GDF15 ameliorates diabetic endothelial dysfunction and oxidative stress by AMPK-dependent pathways in endothelial cells. These results highlight GDF15 as a promising therapeutic target for mitigating oxidative stress and preserving diabetic endothelial dysfunction.

AMPK; Diabetes; Endothelial function; Growth differentiation factor 15; Reactive oxygen species.