Key result
ML-7 partially improves ex vivo aortic relaxation but fails to improve FMD in obese rabbits.
Why the study?
The mechanisms underlying how obesity causes cardiovascular diseases and impaired endothelium-dependent relaxation remain incompletely understood.
Does MLCK inhibition with ML-7 improve endothelium-dependent relaxation in a rabbit model of high-fat diet-induced obesity?
Does MLCK inhibition with ML-7 improve endothelium-dependent relaxation in a rabbit model of high-fat diet-induced obesity?
MLCK inhibition partially restores ex vivo endothelium-dependent relaxation in obese rabbits but does not translate to improved in vivo flow-mediated dilation, highlighting the complexity of vascular dysfunction.
Answers are grounded in this paper and cite their sources.
ML-7 shows no in vivo benefit in obese rabbits; leaves open MLCK inhibition as a vascular target.
Objective Obesity is an independent risk factor for cardiovascular diseases and elevated mortality, yet the underlying mechanisms remain incompletely understood. Impaired endothelium-dependent relaxation is an early manifestation of vascular injury. This study investigated the impact of high-fat diet (HFD)-induced obesity on endothelium-dependent relaxation function and explored the potential role of myosin light chain kinase (MLCK) signaling in a rabbit model. Methods Forty-five male New Zealand White rabbits were randomized into control (normal diet), HFD, and ML-7 (HFD plus the MLCK inhibitor ML-7, 1 mg/kg/day) groups ( n = 15/group). After 8 weeks, in vivo endothelial function was assessed by flow-mediated dilation (FMD) of the iliac artery. Serum lipids and fasting glucose levels were measured. Ex vivo endothelium-dependent and endothelium-independent relaxations were evaluated in aortic rings using cumulative concentrations of acetylcholine (ACh, 0.001–10 μmol/L) and sodium nitroprusside (SNP). Aortic protein expression levels of MLCK, endothelial nitric oxide synthase (eNOS), and phosphorylated myosin light chain (p-MLC) were analyzed by Western blotting. Results HFD-fed rabbits developed obesity (body weight +27.85% vs. control), dyslipidemia (elevated TC, LDL-C, and ox-LDL; all P < 0.001), hyperglycemia ( P < 0.05), and significant endothelial dysfunction, characterized by impaired FMD ( P < 0.05) and reduced ACh-induced relaxation of aortic rings. This was accompanied by increased aortic MLCK expression ( P < 0.001) and a higher p-MLC/MLC ratio ( P < 0.001), whereas eNOS expression and arterial NO levels remained unchanged. ML-7 treatment significantly reduced MLCK expression and MLC phosphorylation. ML-7 partially improved ACh-induced relaxation in aortic rings at higher concentrations (1 and 10 μmol/L, P < 0.05 vs. HFD) but failed to enhance FMD in the iliac artery in vivo . SNP-induced, endothelium-independent relaxation was similar across all groups. Conclusions Obesity-induced endothelial dysfunction is associated with visceral fat accumulation, dyslipidemia, and MLCK upregulation. MLCK inhibition with ML-7 partially restored endothelium-dependent relaxation ex vivo in a concentration-dependent manner but did not translate to improved FMD in vivo . This dissociation highlights the complex nature of vascular dysfunction and suggests that noninvasive FMD may not capture modest, pathway-specific improvements, warranting caution in its use as a sole surrogate for endothelial health in preclinical studies.
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Li et al. (2026) studied High-fat diet-induced obesity and endothelial dysfunction (n=45). ML-7 vs. High-fat diet (HFD) alone and normal diet control was evaluated on Ex vivo endothelium-dependent relaxation (ACh-induced aortic ring relaxation) (p=<0.05). In high-fat diet-induced obese rabbits, the MLCK inhibitor ML-7 partially improved ex vivo endothelium-dependent aortic relaxation at higher acetylcholine concentrations (P < 0.05) but did not improve in vivo flow-mediated dilation.
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