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.
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to cardiac fibrosis and heart failure (HF). Recent studies have demonstrated that EndMT is regulated by autophagy, and we ...previously showed suppression of excessive autophagy and alleviation of cardiac fibrosis in HF mice with inactivated receptor for advanced glycation end products (RAGE). Thus, we investigated whether reduced cardiac fibrosis due to RAGE knockout occurred by inhibiting EndMT mediated by excessive autophagy. We found a decrease in endothelial cells (CD31
/VE-Cadherin
) and an increase in cells co-expressing CD31 and α-smooth muscle actin (α-SMA, myofibroblast marker) at 8 weeks in heart tissue of mice subjected to transverse aortic constriction (TAC), which implied EndMT. Knockout RAGE decreased EndMT accompanied by decreased expression of autophagy-related proteins (LC3BII/I and Beclin 1), and alleviated cardiac fibrosis and improved cardiac function in TAC mice. Moreover, 3-methyladenine (3-MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT, and cardiac fibrosis in TAC mice. Importantly, EndMT induced by AGEs could be blocked by autophagy inhibitor in vivo and in vitro. These results suggested that AGEs/RAGE-autophagy-EndMT axis involved in the development of cardiac fibrosis and knockout RAGE ameliorated cardiac fibrosis through decreasing EndMT regulated by autophagy, which could be a promising therapeutic strategy for HF.
The receptor for advanced glycation end products (RAGE) is involved in heart failure (HF) by mediating diverse pathologic processes, including the promotion of inflammation and autophagy. However, ...the role of RAGE in pressure overload-induced HF is not well understood. We found that stimulation of RAGE triggered the death of neonatal rat ventricular myocytes (NRVMs), while cell death was alleviated by ATG5 knockdown. Using transverse aortic constriction (TAC) in mice as a model of pressure overload-induced HF, we demonstrated that RAGE knockout or RAGE blockade attenuated cardiac hypertrophy and fibrosis as well as cardiac dysfunction at 8 weeks after TAC. Importantly, RAGE knockout reversed upregulation of autophagy related proteins (LC3BII/I and Beclin 1) and reduced cardiomyocyte death, indicating that excessive autophagy after TAC was inhibited. Moreover, RAGE knockout or blockade reduced the upregulation of pp65-NFκB and BNIP3, which mediate autophagy. Taken together, these results suggest that RAGE plays an important role in the progression of HF by regulating autophagy. Therefore, inhibition of the RAGE-autophagy axis could be a promising new strategy for treatment of heart failure.
Abstract only
Endothelial‐to‐mesenchymal transition (EndMT) has been found involved in the progression of heart failure (HF), which maybe one of the source of myofibroblasts. Emerging evidence ...support the notion that EndMT was regulated by autophagy. Our previous studies demonstrated deletion of receptor for advanced glycation end products (RAGE) inhibited autophagy and attenuated cardiac fibrosis in HF. Thus, here we investigated whether reduction of cardiac fibrosis by ablation of RAGE was through inhibition autophagy medicated EndMT. Using transverse aortic constriction (TAC) in mice as a model of pressure overload induced HF, we demonstrated that EndMT and autophagy were induced simultaneously at 8 weeks after TAC. Co‐localization of CD31 and α‐smooth muscle actin (α‐SMA) was observed in myocardium. Knockout of RAGE displayed reduced cardiac fibrosis and significantly improved cardiac function in TAC mice. Importantly, knockout of RAGE deceased the expression of autophagy related proteins (LC3BII/I and Beclin1), which was accompanied with the decrease of co‐expression of CD31 and α‐SMA in TAC mouse hearts. Moreover, 3‐methyladenine (3‐MA) and chloroquine (CQ), inhibitors of autophagy, attenuated EndMT and cardiac fibrosis in TAC mice. Taken together autophagy inducing EndMT may contribute to the development of cardiac fibrosis. Inhibition of this process by RAGE deletion lead to cardiac function improvement and reduction of cardiac fibrosis. Thus, we concluded that inhibition of the RAGE‐autophagy‐EndMT axis could be a novel strategy for treatment of heart failure.
Support or Funding Information
The National Natural Science Foundation of China (81373570, 81673920, 81473621, 81673796 and 81973776). The Natural Science Foundation of Guangdong Province(2016A030311030).
Reduction of cardiac fibrosis especially cardiovascular fibrosis after TAC by inhibition of RAGE and autophagy (Scale bar= 1,000 μm.
n
= 4. Values are shown as means ± SEM, *
P
< 0.05 vs Sham group, #
P
< 0.05 vs TAC group.)
Figure 1
Deceased expression of autophagy and EndMT after TAC by inhibition of RAGE and autophagy. (
n
= 4. Values are shown as means ± SEM, *
P
< 0.05 vs Sham group, #
P
< 0.05 vs TAC group.)
Figure 2
New Findings
What is the central question of this study?
Does the advanced glycation end products (AGEs)–receptor for advanced glycation end products (RAGE) axis mediate myocardial fibrosis in heart ...failure?
What is the main finding and its importance?
The AGEs–RAGE axis is involved in the pathogenesis of myocardial fibrosis through activation of cardiac fibroblasts induced by autophagy in heart failure. By suppression of cardiac fibroblast activation, inhibition of the AGEs–RAGE axis attenuates cardiac dysfunction and myocardial fibrosis in mice with transverse aortic constriction.
Heart failure is the end stage of cardiovascular disease and is a critical medical condition that poses an important therapeutic challenge for physicians owing to its high morbidity and mortality. Myocardial fibrosis is part of the remodelling process that occurs in heart failure. Many studies have shown that advanced glycation end products (AGEs) and receptor for advanced glycation end products (RAGE) are implicated in fibrosis and autophagy, but the mechanism remains unclear. In this study, we elucidated the mechanism by which the AGEs–RAGE axis mediates activation of cardiac fibroblasts (CFs) in heart failure. We used C57BL/6J wild‐type (WT) mice to establish a model of heart failure by transverse aortic constriction (TAC). After 6 weeks of treatment, relevant indicators were detected. In mice subjected to TAC, AGEs were upregulated compared with sham‐operated mice. Inhibition of RAGE resulted in functional cardiac protection, with reduced hypertrophy and fibrosis in mice after TAC. Of note, autophagy mediated the activation of CFs that transformed to myofibroblasts and contributed to fibrosis. In vitro, CFs were obtained from neonatal Sprague–Dawley rats and treated with AGEs, bovine serum albumin and short hairpin RNA (shRNA) for RAGE, in order to verify the results obtained in vivo. These results suggest that the AGEs–RAGE axis is involved in the pathogenesis of myocardial fibrosis in heart failure through CF activation induced by autophagy. Inhibition of the AGEs–RAGE axis attenuates cardiac dysfunction and myocardial fibrosis in mice with TAC by suppressing CF activation.
Myocardial fibrosis (MF) is the characteristic pathological feature of various cardiovascular diseases that lead to heart failure (HF) or even fatal outcomes. Alternatively, activated macrophages are ...involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)‐induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild‐type mice. Our data suggest that mice with macrophage‐specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our in vitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co‐culture system, in vitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of α‐smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast‐to‐myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.
This study reveals the involvement of macrophage RAGE. Activation of RAGE in the heart following TAC surgery affects the autophagic pathway within macrophages, resulting in enhanced autophagic activity. This process ultimately promotes the polarization of macrophages toward the M2 phenotype. Polarized macrophages can induce the transformation of cardiac fibroblasts into myofibroblasts, thereby triggering the process of myocardial fibrosis. This fibrotic remodeling disrupts normal cardiac function, contributing to the development and progression of heart failure.
To investigate whether and how organic anion transporter 1 (OAT1) is involved in the process of Alzheimer’s disease (AD), we crossbred OAT1 knockout mice with tg2576, the widely used AD model mice. ...Results here showed the heterozygous OAT1-deficient tg2576 mice developed a learning- and memory-related behavior deficiency and higher soluble Abeta amount in early stage (3 months old). Furthermore, the heterozygous mice brain slice also showed impaired long-term potentiation (LTP) and spontaneous excitatory postsynaptic currents (sEPSC). By crossbreeding heterozygous OAT1-deficient tg2576 mice with Thy-1 YFP mice, we got autofluoresced (layer 4/5 cortical neuron) heterozygous mice. By using two-photon microscope in the direct observation of mice brain in vivo or single photon confocal on slices, compared with control tg2576 mice, we found that the OAT1-deficient mice showed a higher spine numbers but with a much lesser maturity extent. Finally, by using glutamate uncaging method, we induced chemical LTP in brain slices and found that OAT1-deficient mice showed abnormal chemical-induced LTP, which meant that the deficient behavior may be caused by abnormal spine morphology and activity. Our results indicated OAT1 may be involved in AD process by regulating spine morphology and activity.
To investigate how organic anion transporter (OAT)-1 is involved in uric acid nephropathy (UAN), a rat model for UAN was established and the serum uric acid, blood urea nitrogen and serum creatinine ...levels were all measured, and observed to be increased. It was additionally identified that in UAN rats the surface OAT1 expression levels were reduced. By treating HEK cells with monosodium urate (MSU) crystals, it was observed that the cells exhibited a reduction in OAT1 levels. Furthermore, MSU crystals were observed to recruit Ras homolog family member A (RhoA), a small guanosine triphosphatase, to the membrane and activate it. Following RhoA activation, the OAT1 internalization rate was identified to be increased. The dominant‑negative RhoA N19 mutation was able to block MSU‑induced OAT1 internalization, indicating that the process was RhoA‑dependent. Finally, the results indicated that folic acid, a daily nutritional supplement, was capable of rescuing MSU‑induced nephropathy and OAT1 internalization. These observations indicated that uric acid crystals were able to reduce the OAT1 membrane distribution through activating RhoA, and that folic acid was capable of preventing MSU-induced OAT1 relocation by inhibiting the RhoA signaling pathway.
To develop Clinical Practice Guidelines for the screening, assessment and management of the geriatric condition of frailty.
An adapted Grading of Recommendations, Assessment, Development, and ...Evaluation approach was used to develop the guidelines. This process involved detailed evaluation of the current scientific evidence paired with expert panel interpretation. Three categories of Clinical Practice Guidelines recommendations were developed: strong, conditional, and no recommendation.
Strong recommendations were (1) use a validated measurement tool to identify frailty; (2) prescribe physical activity with a resistance training component; and (3) address polypharmacy by reducing or deprescribing any inappropriate/superfluous medications. Conditional recommendations were (1) screen for, and address modifiable causes of fatigue; (2) for persons exhibiting unintentional weight loss, screen for reversible causes and consider food fortification and protein/caloric supplementation; and (3) prescribe vitamin D for individuals deficient in vitamin D. No recommendation was given regarding the provision of a patient support and education plan.
The recommendations provided herein are intended for use by healthcare providers in their management of older adults with frailty in the Asia Pacific region. It is proposed that regional guideline support committees be formed to help provide regular updates to these evidence-based guidelines.
Congenital asymmetric crying facies (ACF) in newborns is a rare condition usually caused by unilateral agenesis or hypoplasia of the depressor anguli oris muscle on one side of the mouth (symmetric ...face at rest and asymmetric face while crying), which is often accompanied with other malformations.
We present a case of a female newborn with nonconsanguineous ethnic Han Chinese parents who presented with 37 minutes of breathlessness and asymmetrical face when crying. A thorough physical examination had been conducted. The patient was diagnosed with aspiration pneumonia and congenital ACF syndrome, accompanied with congenital bilateral anophthalmia, left homolateral auricle dysplasia, malformation in the left-hand thumb, patent ductus arteriosus (PDA), and patent foramen ovale (PFO) and tracheoesophageal fistula. The patient's mother underwent routine fetal sonogram at 25 weeks gestation, which showed major anatomical anomalies in the eyes of the fetus. The mother chose to pregnancy until vaginal delivery. This case is unique because congenital bilateral anophthalmia has not been reported in such patients before.
Careful physical examination of newborns and genetic testing are important for early diagnosis of neonatal asymmetric crying facies (NACF), especially if ACF is present. Early determination of the etiology and future screenings are very important for the management of this condition. The lower lip on the affected side looks thinner because of the lack of the muscle agenesis, so the use of ultrasound to observe facial muscles and electrodiagnostic testing could be helpful for the differential diagnosis of NACF from congenital facial nerve dysplasia.
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