Abstract
BackgroundToll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system. TLR4 contributes to many aging-related chronic diseases. However, whether TLR4 is involved in cardiovascular injury during the aging process has not been investigated.MethodsThe effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4−/− mice. An intraperitoneal glucose tolerance test (IPGTT) and insulin sensitivity test (IST) were conducted to evaluate global insulin sensitivity. Echocardiography was used to measure cardiac structure and performance. An isolated artery ring assay was used to measure the vasodilator function of the thoracic aorta. The inflammatory response was reflected by the serum concentration of cytokines.ResultsTLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency.ConclusionIn summary, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.
Highlights
With the improvement of health care, the lifespan of humans has been extended, and the elderly population is increasing globally [1]
Protein expression of Toll-like receptor 4 (TLR4) increased in the aged hearts and aortas of mice To determine whether TLR4 is related to cardiovascular dysfunction associated with aging, we measured the protein expression of TLR4 in the hearts and aortas of mice at different ages
Effects of loss of TLR4 on insulin sensitivity and lipid profile in aged mice fasting blood glucose was not different between the Young and Aged groups (Fig. 2A), the intraperitoneal glucose tolerance test (IPGTT) (Fig. 2B and C) and insulin sensitivity test (IST) (Fig. 2D and E) results indicated a significant reduction in whole-body insulin sensitivity
Summary
With the improvement of health care, the lifespan of humans has been extended, and the elderly population is increasing globally [1]. Aging is an independent risk factor for cardiovascular diseases, which contribute to the increased morbidity and mortality in the aging population [7]. When sensing DAMPs, TLR4 triggers intracellular signaling pathways in a MyD88-dependent and MyD88-independent manner, which subsequently activates downstream inflammatory responses, leading to the release of inflammatory factors [16]. The TLR4 pathway has been reported to be related to chronic inflammation and the progression of a variety of diseases, such as diabetes, cardiovascular diseases, and even cancer [18,19,20,21]. Whether TLR4 contributes to cardiovascular injury during the aging process has not been investigated. TLR4 contributes to many aging-related chronic diseases. Whether TLR4 is involved in cardiovascular injury during the aging process has not been investigated. The inflammatory response was reflected by the serum concentration of cytokines
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