Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1868, Issue 2, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2021.166301
Keywords
Myeloid differentiation factor 2; L6H21; Heart; Apoptosis; Ferroptosis; Prediabetes
Funding
- Thailand Science Research and Innovation [DBG6280006]
- National Natural Science Foundation of China [21961142009]
- NSTDA Research Chair Grant from the National Science and Technology Development Agency Thailand
- National Research Council of Thailand (SCC)
- Chiang Mai University Center of Excellence Award
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The study found that L6H21 has a protective effect on cardiac function in prediabetic rats, reducing cardiac inflammation and cell death caused by prediabetes, and this effect is dose- and time-dependent.
Systemic inflammation is a key mediator of left ventricular dysfunction (LV) in prediabetes via the activation of myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex. The MD2 inhibitor L6H21 effectively reduced systemic and cardiac inflammation in obese mice. However, its effects on cardiac function and regulated cell death pathways in the heart in prediabetes are still unknown. The prediabetic rats were divided into 3 subgroups to receive vehicle, L6H21 (10, 20, 40 mg/kg) or metformin (300 mg/kg) for 1, 2 and 4 weeks. Then, metabolic parameters, cardiac sympathovagal balance, LV function, cardiac mitochondrial function, oxidative stress, inflammation, apoptosis, necroptosis, and ferroptosis were determined. All prediabetic rats exhibited cardiac sympathovagal imbalance, LV dysfunction, and cardiac mitochondrial dysfunction. All doses of L6H21 treatment for 2- and 4-weeks attenuated insulin resistance. L6H21 at 40 mg/kg attenuated cardiac autonomic imbalance and LV dysfunction after 1 week of treatment. Both 10 and 20 mg/kg of L6H21 required longer treatment duration to show these benefits. Mechanistically, all doses of L6H21 reduced cardiac mitochondrial dysfunction after 1 week of treatment, resulting in alleviated oxidative stress and inflammation. L6H21 also effectively suppressed cardiac apoptosis and ferroptosis, but it did not affect necroptosis in prediabetic rats. L6H21 provided the cardioprotective efficacy in dose- and time-dependent manners in prediabetic rats via reduction in apoptosis and ferroptosis.
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