Deficiency of the Immunoproteasome LMP10 Subunit Attenuates Angiotensin II-Induced Cardiac Hypertrophic Remodeling via Autophagic Degradation of gp130 and IGF1R

Wen, Yiping; Dong, Zhi-Chao; Wang, Jingjing; Zhang, Yun-Long; Wang, Hongxia; Zhang, Bo; Li, Huihua

doi:10.3389/fphys.2020.00625

Cited by 8 publications

(5 citation statements)

References 37 publications

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“…To determine the molecular mechanism underpinning the beneficial effect of HHP-EXO, the cardiac hypertrophy-associated signaling molecules β-MHC, BNP, GP130, p-ERK1/2, p-AKT, and p-STAT3 [ 21 ] were analyzed in ventricular tissues of mice with different treatments. The protein expression of β-MHC, BNP, GP130, p-ERK1/2, p-AKT, and p-STAT3 was significantly up-regulated in TAC mice treated with PBS (n = 6, P < 0.01 vs sham mice), and the increased protein levels were significantly decreased in TAC mice receiving HHP-EXO (n = 6, P < 0.01 vs PBS), while only β-MHC, GP130, and p-STAT3 were decreased in TAC mice treated with CON-EXO (n = 6, P < 0.05) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy

Liang

Chen

et al. 2022

J Nanobiotechnol

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Exosomes of human cardiosphere-derived cells (CDCs) are very promising for treating cardiovascular disorders. However, the current challenge is inconvenient delivery methods of exosomes for clinical application. The present study aims to explore the potential to enhance the therapeutic effect of exosome (EXO) from human CDCs to myocardial hypertrophy. A heart homing peptide (HHP) was displayed on the surface of exosomes derived from CDCs that were forced to express the HHP fused on the N-terminus of the lysosomal-associated membrane protein 2b (LAMP2b). The cardiomyocyte-targeting capability of exosomes were analyzed and their therapeutic effects were evaluated in a mouse model of myocardial hypertrophy induced by transverse aorta constriction (TAC). The molecular mechanisms of the therapeutic effects were dissected in angiotensin II-induced neonatal rat cardiomyocyte (NRCMs) hypertrophy model using a combination of biochemistry, immunohistochemistry and molecular biology techniques. We found that HHP-exosomes (HHP-EXO) accumulated more in mouse hearts after intravenous delivery and in cultured NRCMs than control exosomes (CON-EXO). Cardiac function of TAC mice was significantly improved with intravenous HHP-EXO administration. Left ventricular hypertrophy was reduced more by HHP-EXO than CON-EXO via inhibition of β-MHC, BNP, GP130, p-STAT3, p-ERK1/2, and p-AKT. Similar results were obtained in angiotensin II-induced hypertrophy of NRCMs, in which the beneficial effects of HHP-EXO were abolished by miRNA-148a inhibition. Our results indicate that HHP-EXO preferentially target the heart and improve the therapeutic effect of CDCs-exosomes on cardiac hypertrophy. The beneficial therapeutic effect is most likely attributed to miRNA-148a-mediated suppression of GP130, which in turn inhibits STAT3/ERK1/2/AKT signaling pathway, leading to improved cardiac function and remodeling.

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Section: Resultsmentioning

confidence: 99%

Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy

Liang

Chen

et al. 2022

J Nanobiotechnol

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“…It is important to note that dysregulation of autophagy may play an important role in AngII-induced cardiac stress although conflicting reports exists regarding this issue 26 . Interestingly, several studies (e.g., 47 ) demonstrate a cooperation between the ubiquitin–proteasome system (UPS) and lysosomal-autophagy pathway. In this regard, our results may also raise the possibility that the UPS, rather than the autophagy-lysosome pathway, is responsible for maintaining cardiac function following AngII when the lysosomal-autophagy process is dysregulated.…”

Section: Discussionmentioning

confidence: 99%

Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts

Etzion,

Hijaze,

Segal

et al. 2024

Sci Rep

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Plekhm2 is a protein regulating endosomal trafficking and lysosomal distribution. We recently linked a recessive inherited mutation in PLEKHM2 to a familial form of dilated cardiomyopathy and left ventricular non-compaction. These patients’ primary fibroblasts exhibited abnormal lysosomal distribution and autophagy impairment. We therefore hypothesized that loss of PLEKHM2 impairs cardiac function via autophagy derangement. Here, we characterized the roles of Plekhm2 in the heart using global Plekhm2 knockout (PLK2-KO) mice and cultured cardiac cells. Compared to littermate controls (WT), young PLK2-KO mice exhibited no difference in heart function or autophagy markers but demonstrated higher basal AKT phosphorylation. Older PLK2-KO mice had body and heart growth retardation and increased LC3II protein levels. PLK2-KO mice were more vulnerable to fasting and, interestingly, impaired autophagy was noted in vitro, in Plekhm2-deficient cardiofibroblasts but not in cardiomyocytes. PLK2-KO hearts appeared to be less sensitive to pathological hypertrophy induced by angiotensin-II compared to WT. Our findings suggest a role of Plekhm2 in murine cardiac autophagy. Plekhm2 deficiency impaired autophagy in cardiofibroblasts, but the autophagy in cardiomyocytes is not critically dependent on Plekhm2. The absence of Plekhm2 in mice appears to promote compensatory mechanism(s) enabling the heart to manage angiotensin-II-induced stress without detrimental consequences.

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“…Immunoinflammatory activation with excessive systemic action of cytokines and other related autacoids plays an important role in the pathogenesis and progression of heart failure, regardless of the diseases that may lead to it [ 23 , 24 ]. Proinflammatory cytokines contribute to LV remodeling and CHF progression, worsening its contractile function and stimulating the development of LVH, the apoptosis of cardiomyocytes, and fibrosis [ 25 , 26 , 27 ]. Patients with various diseases and pathological processes (in particular, aortic stenosis, hypertrophic cardiomyopathy, heart transplantation) and preserved LVEF are characterized by increased levels of proinflammatory cytokines identified in the myocardium and systemic circulation [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Systemic Action of Inflammatory Mediators in Patients with Essential Hypertension and Diastolic Chronic Heart Failure: A Clinical Pathophysiological Study

et al. 2020

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The aim of this research was to correlate indicators of proinflammatory status and the structural/functional characteristics of the cardiovascular system comparatively in male and female patients with essential hypertension (EH) complicated by diastolic chronic heart failure (CHF) with preserved left ventricular ejection fraction (LVEF). The study included 104 middle-aged patients (55 males (M) and 49 females (F)) with first- or second-degree EH complicated by CHF with preserved LVEF. They all belonged to the low functional class of CHF, with LVEF ≥50%, first- or second-degree of LV diastolic dysfunction (LVDD), LV hypertrophy (LVH), and dilatation of the left atrium (LA) with a sinus rhythm and N-terminal brain natriuretic peptide >125 pg/mL. Serum levels of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) were measured. To identify the relationship between the proinflammatory pattern and cardiovascular parameters, Spearman’s rank correlation coefficients were determined. M had markedly higher levels of CRP, TNF-α, and IL-6 compared to F. However, all the mean values corresponded to the reference range. Significant direct associations of CRP level with the LV mass index (LVMI), relative wall thickness (RWT), LA volume index (LAVI), E/e’ ratio, and systolic and diastolic blood pressure (SBP, DBP) existed in both M and F, as well as negative correlations of CRP with LVDD parameter e’ and distance covered in a 6 min walk test. M and F had a positive association between IL-6 and LVMI, LAVI, E/e’ ratio, SBP, RWT, and DBP, as well as strong negative associations between IL-6 and e’ and distance passed in 6 min in each group. Significant direct correlations existed between serum TNF-α level and LVMI, RWT, LAVI, E/e’, SBP, and DBP both in M and F. Furthermore, there were negative relationships of TNF-α level with e’ and the distance covered for the 6 min walk. This study demonstrated a close relationship between the blood levels of proinflammatory autacoids and indicators of EH, exercise tolerance, LVH, LVDD, and LA enlargement, regardless of the patient’s sex. Compared to female patients, male patients had stronger correlations of CRP, TNF-α, and IL-6 levels with indicators of LVDD degree.

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Deficiency of the Immunoproteasome LMP10 Subunit Attenuates Angiotensin II-Induced Cardiac Hypertrophic Remodeling via Autophagic Degradation of gp130 and IGF1R

Cited by 8 publications

References 37 publications

Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy

Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy

Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts

Systemic Action of Inflammatory Mediators in Patients with Essential Hypertension and Diastolic Chronic Heart Failure: A Clinical Pathophysiological Study

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