scholarly journals Protection of Sacubitril/Valsartan against Pathological Cardiac Remodeling by Inhibiting the NLRP3 Inflammasome after Relief of Pressure Overload in Mice

2020 ◽  
Vol 34 (5) ◽  
pp. 629-640
Author(s):  
Xueling Li ◽  
Qin Zhu ◽  
Qingcheng Wang ◽  
Qinggang Zhang ◽  
Yaru Zheng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Myocardial Cell ◽  
Heart Weight ◽  
Inflammasome Activation ◽  
Clinical Prognosis ◽  
Nlrp3 Inflammasome Activation ◽  
Neprilysin Inhibitor

Abstract Background/aims The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice. Methods and results Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload. Conclusion Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.

scholarly journals Triptolide Inhibits the Activation of NLRP3 Inflammasome by Inhibiting NF-κB Pathway and Improves Myocardial Fibrosis

2021 ◽  
Author(s):  
Jianyao Shen ◽  
Hailiang Ma ◽  
Chaoquan Wang
Keyword(s):  
Myocardial Fibrosis ◽  
Nlrp3 Inflammasome ◽  
Subcutaneous Injection ◽  
Tissue Injury ◽  
Myocardial Cell ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Related Factors ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α

Abstract ObjectiveTriptolide (TPL) is identified to be involved in the treatment for myocardial fibrosis (MF). This study investigated the mechanism of TPL in MF in rats and observed its effect on NLRP3 inflammasome signaling pathway.Materials and MethodsThe MF rat model was established by subcutaneous injection of isoproterenol (ISO), and treated by subcutaneous injection of TPL. After modeling for 1 week, the cardiac function of rats was evaluated, including LVEF, LVFS, LVES, LVED LVIDs and LVPWs. The HMI and LVMI were measured. The expressions of ANP, BNP, inflammatory related factors (IL-1β, IL-18, TNF-α, MCP-1, VCAM-1), and NLRP3 inflammasome factors (NLRP3, ASC, caspase-1) in rats were detected. HE staining and Masson staining were used to observe myocardial cell inflammation and fibrosis of rats.ResultsLVED, LVES, LVIDs and LVPWs of MF group were significantly upregulated, LVEF and LVFS were significantly downregulated, HMI and LVMI were upregulated, while TPL treatment reversed these trends; TPL treatment downregulated the tissue injury and improved the pathological damage of MF rats. TPL treatment downregulated the levels of inflammatory factors and fibrosis factors, and inhibited the activation of NLRP3 inflammasome. Activation of NLRP3 inflammasome or NF-κB pathway reversed the effect of TPL on MF.ConclusionsTPL inhibited the activation of NLRP3 inflammasome by inhibiting NF-κB pathway, and improved the degree of MF in MF rats.

scholarly journals Tumor-Targeted Drug Delivery as a Successful Approach for Reducing Doxorubicin–Induced Cardiotoxicity

2021 ◽  
Author(s):  
Nasibeh Mohammad Ali Pourradi ◽  
Yadollah Azarmi ◽  
Hossien Babaei ◽  
Behzad Baradaran ◽  
Behrooz Shokouhi-Gogani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Nlrp3 Inflammasome ◽  
Targeted Drug Delivery ◽  
Left Ventricular ◽  
Heart Weight ◽  
Inflammasome Activation ◽  
Body Distribution ◽  
Nlrp3 Inflammasome Activation ◽  
Targeted Drug

Abstract Doxorubicin (DOX) is an effective chemotherapy drug used to treat many malignancies, including breast cancer. However, its clinical application is severely limited by cardiotoxicity. This study investigated if using thermo/pHsensitive magnetic nanoparticles decorated with folate (folate-poly-MNPs) as tumor-targeted drug delivery systems (DDSs) could reduce the cardiotoxicity and inflammatory properties of DOX in a rat model of breast cancer. In this study, forty rats were intravenously administered the control, DOX, DOX-poly-MNPs, and DOXfolate-poly-MNPs every 48 hours for 12 days. The cardiac health monitoring following breast cancer therapy confirmed that the novel smart DDS improved ECG pattern, left ventricular function, blood pressure parameters, and heart weight index. Moreover, it could decrease myocardial cell death by decreasing the protein levels of BAX, c-PARP1, and c-caspase-3, with concomitant downregulation of the BAX/Bcl-2 ratio, compared to the commercial DOX. In addition, the DOXfolate-poly-MNPs treatment significantly reduced NLRP3 inflammasome activation in cardiomyocytes, which was mediated by caspase-1 inhibition, and suppressed upregulation of IL-1β and IL18 protein expression to prevent myocardial damage. In this regard, the developed folatepolyMNPs could be represented as a new potential drug delivery system for breast cancer chemotherapy due to the combination of passive and active targeting aimed at preventing nonspecific body distribution, inhibiting NLRP3 inflammasome activation, and consequently reducing DOX cardiotoxicity as its main adverse effect.

scholarly journals Intermedin1-53 Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis

2021 ◽  
Author(s):  
Lin-Shuang Zhang ◽  
Jin-Sheng Zhang ◽  
Yue-Long Hou ◽  
Wei-Wei Lu ◽  
Xian-Qiang Ni ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cardiac Fibrosis ◽  
Underlying Mechanism ◽  
Inflammasome Activation ◽  
Rat Myocardium ◽  
Ang Ii ◽  
Receptor System ◽  
Nlrp3 Inflammasome Activation ◽  
Pka Pathway

Abstract Intermedin (IMD), a paracrine/autocrine peptide, protects against cardiac fibrosis. However, the underlying mechanism remains poorly understood. Previous study reports that activation of Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributed to cardiac fibrosis. In this study, we aimed to investigate whether IMD mitigates cardiac fibrosis by inhibiting NLRP3. Cardiac fibrosis was induced by angiotensin II (Ang II) infusion for 2 weeks in rats. Western blot, real-time PCR, histological staining, immunofluorescence assay, RNA sequencing, echocardiography and hemodynamics were used to detect the role and the mechanism of IMD in cardiac fibrosis. Ang II infusion resulted in rat cardiac fibrosis, shown as over-deposition of myocardial interstitial collagen and cardiac dysfunction. Importantly, NLRP3 activation and endoplasmic reticulum stress (ERS) was found in Ang II treated rat myocardium. Ang II infusion decreased the expression of IMD and increased the expression of the receptor system of IMD in the fibrotic rat myocardium. IMD treatment attenuated the cardiac fibrosis and improved cardiac function. In addition, IMD inhibited the upregulation of NLRP3 markers and ERS markers induced by Ang II. In vitro, IMD knockdown by small interfering RNA significantly promoted the Ang II-induced cardiac fibroblast and NLRP3 activation. Moreover, silencing of inositol requiring enzyme 1 α (IRE1α) blocked the effects of IMD inhibiting fibroblast and NLRP3 activation. Pre-incubation with PKA pathway inhibitor H89 blocked the effects of IMD on the anti-ERS, anti-NLRP3 and anti-fibrotic response. In conclusion, IMD alleviates cardiac fibrosis by inhibiting NLRP3 inflammasome activation via suppressing IRE1α and cAMP/PKA pathway.

scholarly journals Nlrp3 Deficiency Alleviates Angiotensin II-Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yu Chen ◽  
Meiying Zeng ◽  
Yang Zhang ◽  
Hui Guo ◽  
Wei Ding ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Function ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Gene Deletion ◽  
Cardiac Fibrosis ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Nlrp3 Gene ◽  
Nlrp3 Inflammasome Activation

Inflammation has been considered a key component in the pathogenesis and progression of angiotensin II- (Ang II-) induced cardiac hypertrophy and related cardiomyopathy. As a vital mediator of inflammation, the role of the Nlrp3 inflammasome in Ang II-induced cardiomyopathy remains unclear. This study was aimed to determine whether Nlrp3 inflammasome activation and its downstream pathway were involved in Ang II-induced cardiomyopathy. We established an Ang II infusion model in both wild-type and Nlrp3-/- mice to determine the contribution of Nlrp3 to cardiac function. Cardiac fibrosis was determined by Masson’s trichrome staining, real-time PCR, and TUNEL assay; cardiac function was assessed by echocardiography. Nlrp3 inflammasome activation and related downstream cytokines were measured by Western blotting and enzyme-linked immunosorbent assays; mitochondrial dysfunction was examined by transmission electron microscopy and real-time PCR. We found that Ang II-infused mice showed impaired cardiac function, as evidenced by increased cardiac fibrosis, apoptosis, inflammation, and left ventricular dysfunction. However, these alterations were significantly alleviated in the mice with Nlrp3 gene deletion. Moreover, Ang II-infused mice showed increased Nlrp3 inflammasome activity relative to that of the cytokines IL-1β and IL-18, increased reactive oxygen species, mitochondrial abnormalities, and decreased mtDNA copy number and ATP synthase activity. These molecular and pathological alterations were also attenuated in Nlrp3 deficient mice. In conclusion, Nlrp3 inflammasome-induced mitochondrial dysfunction is involved in Ang II-induced cardiomyopathy. Nlrp3 gene deletion attenuated mitochondrial abnormalities, cardiac inflammation, oxidative stress, and fibrosis and thus alleviated heart dysfunction and hypertrophy. Targeting the Nlrp3 inflammasome and/or mitochondria may be a therapeutic approach for Ang II-induced cardiac diseases.

Abstract 536: Human Antigen R (HuR) in the Myofibroblasts is a Critical Regulator of Pressure-Overload Induced Cardiac Remodeling

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Lisa Green ◽  
Sarah Anthony ◽  
Perwez Alam ◽  
Michael Tranter
Keyword(s):  
Cardiac Function ◽  
Small Molecule ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Small Molecule Inhibitor ◽  
Heart Weight ◽  
Ecm Remodeling ◽  
Human Antigen R ◽  
Molecule Inhibitor

Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) and is an important target because excess ECM leads to a stiffened myocardium and worsens the prognosis of heart failure. Human Antigen R (HuR) is an RNA binding protein known to stabilize mRNA through binding to AU rich regions in the 3’UTR, and we have previously shown HuR to play a central role in the development of cardiac hypertrophy. To interrogate the role of HuR in cardiac fibrosis, we used both a small molecule inhibitor of HuR as well as an inducible genetic deletion of HuR in the activated cardiac myofibroblasts (iMF-HuR -/- ). Results using an in vitro scratch assay showed that primary adult cardiac fibroblasts treated with a small molecule inhibitor of HuR display a delayed wound healing response concomitant with a reduced expression of ECM remodeling genes. In vivo , we used an 8-week TAC (transverse aortic constriction) model of pressure overload to induce pathological cardiac remodeling. We hypothesized that deleting HuR in the activated fibroblasts would dampen myofibroblast-mediated ECM remodeling leading to a less stiff myocardium with reduced fibrotic burden and improved cardiac function in iMF-HuR -/- mice following pressure overload (TAC). However, echocardiography results show that cardiac function declined more rapidly in iMF-HuR -/- following TAC. The iMF-HuR -/- mice also had significantly enlarged hearts compared to the controls indicated by the heart weight/tibia length ratio. This suggests a critical role for HuR and myofibroblast activity in the early response to pressure overload. Future studies will focus on determining how the fibroblasts and the ECM composition/stiffness affect myocyte function in the early cardiac remodeling phase post-TAC and how HuR is involved in this relationship.

Sign in / Sign up

Export Citation Format

Share Document