Abstract
Chronic heart failure (CHF) is the final outcome of many cardiovascular diseases, and is a severe health issue faced by the elderly population. Mixed lineage kinase 3 (MLK3), a member of MAP3K family, is associated with aging, inflammation, oxidative stress, and related diseases, such as CHF. MLK3 has also been reported to play an important role in protecting against cardiomyocyte injury; however, its function in myocardial fibrosis is unknown. To investigate the role of MLK3 in myocardial fibrosis, we inhibited the expression of MLK3, and examined cardiac function and remodeling in TAC mice. In addition, we assessed the expression of MLK3 protein in ventricular cells and its downstream associated protein. We found that MLK3 mainly regulates NF-κB/NLRP3 signaling pathway-mediated inflammation and that pyroptosis causes myocardial fibrosis in the early stages of CHF. Similarly, MLK3 mainly regulates the JNK/p53 signaling pathway-mediated oxidative stress and that ferroptosis causes myocardial fibrosis in the advanced stages of CHF. We also found that promoting the expression of miR-351 can inhibit the expression of MLK3, and significantly improve cardiac function in mice subjected to TAC. These results suggest the pyroptosis and ferroptosis induced by MLK3 signaling in cardiomyocytes are essential for adverse myocardial fibrosis, in response to pressure overload. Furthermore, miR-351, which has a protective effect on ventricular remodeling in heart failure caused by pressure overload, may be a key target for the regulation of MLK3.
Highlights
Chronic heart failure (CHF) characterized by high mortality and morbidity is the final outcome of many cardiovascular diseases[1,2]
The cardiac function of transverse aortic constriction (TAC) mice remained at a significantly reduced level of cardiac function, while URMC-099 mice maintained a stable level, showing a significant increase in left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and a significant decrease in left ventricular internal dimension (LVID); d, LVID; s, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular mass (LV mass) compared with TAC mice at week 4 and 8 (Fig. 1c–i)
We found that LVID; d, LVID; s, LVEDV, LVESV, LV mass, heart size, and collagen deposition were significantly increased, whereas LVEF and LVFS were significantly decreased in TAC and antagomir mice compared with sham mice
Summary
Chronic heart failure (CHF) characterized by high mortality and morbidity is the final outcome of many cardiovascular diseases[1,2]. Like hypertension, Inflammation during the process of myocardial damage and repair leads to collagen deposits to form a collagenbased scar[8,9]. Official journal of the Cell Death Differentiation Association. Wang et al Cell Death and Disease (2020)11:574 it is caused by ischemic or nonischemic damage[10]. The NLRP3 inflammasome can produce interleukin 1β (IL-1β) and IL-1811 and mediate pyroptosis, which is caspase-1-dependent programmed cell death, and is known as inflammatory necrosis[12]. Sano et al.[13,14,15] found that NLRP3 inflammasome-targeted therapies might be effective methods to reduce infarct size and prevent heart failure following AMI and transverse aortic constriction (TAC)
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