Metformin Attenuates Postinfarction Myocardial Fibrosis and Inflammation in Mice.
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ABSTRACT:
SUBMITTER: Loi H
PROVIDER: S-EPMC8430638 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2-positive fibroblasts, while the number of c-kit(+) cardiac stem cells and Ki-67(+) proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure.
| S-EPMC4186442 | biostudies-literature
Project description:Corosolic acid (CRA) is a pentacyclic triterpenoid isolated from Lagerstroemia speciosa. The aim of the present study was to determine whether CRA reduces cardiac remodelling following myocardial infarction (MI) and to elucidate the underlying mechanisms. C57BL/6J mice were randomly divided into control (PBS?treated) or CRA?treated groups. After 14 days of pre?treatment, the mice were subjected to either sham surgery or permanent ligation of the left anterior descending artery. Following surgery, all animals were treated with PBS or CRA (10 or 20 mg/kg/day) for 4 weeks. After 4 weeks, echocardiographic, haemodynamic, gravimetric, histological and biochemical analyses were conducted. The results revealed that, upon MI, mice with CRA treatment exhibited decreased mortality rates, improved ventricular function and attenuated cardiac fibrosis compared with those in control mice. Furthermore, CRA treatment resulted in reduced oxidative stress, inflammation and apoptosis, as well as inhibited the transforming growth factor ?1/Smad signalling pathway activation in cardiac tissue. In vitro studies further indicated that inhibition of AMP?activated protein kinase ? (AMPK?) reversed the protective effect of CRA. In conclusion, the study revealed that CRA attenuated MI?induced cardiac fibrosis and dysfunction through modulation of inflammation and oxidative stress associated with AMPK?.
| S-EPMC7138284 | biostudies-literature
Project description:Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg-1·d-1, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg-1·d-1, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGF?-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.
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Project description:The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.
| S-EPMC8474861 | biostudies-literature
Project description:Aims:Cardiac inflammation has been suggested to be regulated by the sympathetic nervous system (SNS). However, due to the lack of methodology to surgically eliminate the myocardial SNS in mice, neuronal control of cardiac inflammation remains ill-defined. Here, we report a procedure for local cardiac sympathetic denervation in mice and tested its effect in a mouse model of heart failure post-myocardial infarction. Methods and results:Upon preparation of the carotid bifurcation, the right and the left superior cervical ganglia were localized and their pre- and postganglionic branches dissected before removal of the ganglion. Ganglionectomy led to an almost entire loss of myocardial sympathetic innervation in the left ventricular anterior wall. When applied at the time of myocardial infarction (MI), cardiac sympathetic denervation did not affect acute myocardial damage and infarct size. In contrast, cardiac sympathetic denervation significantly attenuated chronic consequences of MI, including myocardial inflammation, myocyte hypertrophy, and overall cardiac dysfunction. Conclusion:These data suggest a critical role for local sympathetic control of cardiac inflammation. Our model of myocardial sympathetic denervation in mice should prove useful to further dissect the molecular mechanisms underlying cardiac neural control.
| S-EPMC5852629 | biostudies-literature
Project description:Premature decidual senescence is a contributing factor to preterm birth. Fatty acid amide hydrolase mutant females (Faah-/-) with higher endocannabinoid levels are also more susceptible to preterm birth upon lipopolysaccharide (LPS) challenge due to enhanced decidual senescence; this is associated with mitogen-activated protein kinase p38 activation. Previous studies have shown that mechanistic target of rapamycin complex 1 (mTORC1) contributes to decidual senescence and promotes the incidence of preterm birth. In this study, we sought to attenuate premature decidual aging in Faah-/- females by targeting mTORC1 and p38 signaling pathways. Because metformin is known to inhibit mTOR and p38 signaling pathways, Faah-/- females were treated with metformin. These mice had a significantly lower preterm birth incidence with a higher rate of live birth after an LPS challenge on day 16 of pregnancy; metformin treatment did not affect placentation or neonatal birth weight. These results were associated with decreased levels of p38, as well as pS6, a downstream mediator of mTORC1 activity, in day 16 Faah-/-decidual tissues. Since metformin treatment attenuates premature decidual senescence with limited side effects during pregnancy, careful use of this drug may be effective in ameliorating specific adverse pregnancy events.
| S-EPMC6248772 | biostudies-literature
Project description:AimsAge-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing.Methods and resultsWe compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n ? 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-? (TGF-?)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8.ConclusionMMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-? signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.
| S-EPMC3500048 | biostudies-literature
Project description:The development of cardiovascular fibrosis is associated with chronic inflammation, where activation of nuclear factor ?B (NF-?B) signaling may play a critical role. NF-?B activation is tightly regulated by the cellular inhibitor of ?B (I?B) family of proteins, such as I?B? and I?B?. I?B? and I?B? display different regulation kinetics in response to inflammatory stimulation. The present study tested the hypothesis that I?B? and I?B? may have different roles in modulating cardiovascular inflammation and fibrosis, using a model of angiotensin II infusion-induced hypertension in wild-type mice and I?B? knock-in mice, in which the I?B? gene is replaced by I?B? cDNA (AKBI). In WT mice, subcutaneous angiotensin II infusion for 7 days induced increased perivascular and interstitial collagen deposition and fibrotic lesions, associated with myocardial interstitial hemosiderin accumulation and extensive macrophage infiltration. These effects of angiotensin II were dramatically limited in AKBI mice. Replacement of I?B? with I?B? significantly attenuated angiotensin II infusion-induced expression of interleukin 1?, interleukin 6, monocyte chemotactic protein 1, collagen I and III, fibronectin, and tissue inhibitor of metalloproteinase 1 in the hearts. Furthermore, using cultured vascular smooth muscle cells, we demonstrated that interleukin 1?-induced NF-?B activation and monocyte chemotactic protein 1, vascular cell adhesion molecule 1, and tissue inhibitor of metalloproteinase 1 expressions were suppressed in the AKBI cells because of the replacement of I?B? with I?B?. These results indicate that NF-?B has an essential role in mediating the cardiovascular inflammatory response to angiotensin II and suggest that targeting the balance of I?B? and I?B? expression might be a novel therapeutic modality in preventing fibrosis in hypertensive cardiovascular disease.
| S-EPMC3141280 | biostudies-literature
Project description:Toll-like receptor 4 (TLR4) signaling plays a key role in liver inflammation and fibrosis. The therapeutic effects of eritoran, a TLR4 antagonist, in mice with chronic liver injury remained unclear. C57BL/6 mice were fed a fast-food diet (FFD) or treated with carbon tetrachloride (CCl4) to induce chronic liver injury. Eritoran (10 mg/kg) or a vehicle was randomly intraperitoneally administered to the FFD-fed mice and the CCl4-injured mice. Primary mouse liver cells were cultured with lipopolysaccharide (LPS) or eritoran. In both FFD and CCl4 mouse models, eritoran significantly reduced serum ALT levels and decreased hepatic inflammatory cell infiltration without altering hepatic steatosis. Additionally, eritoran attenuated liver fibrosis by decreasing hepatic stellate cells (HSCs) activation and the abundance of α-smooth muscle actin and transforming growth factor-β1. Hepatic TLR4 downstream signaling including MyD88 expression, NF-κB p65 nuclear translocation, p38 and JNK phosphorylation were successfully inhibited by eritoran. In the in vitro study, LPS-induced nuclear translocation of NF-κB in primary HSCs and Kupffer cells was significantly suppressed by eritoran. In conclusion, eritoran attenuated hepatic inflammation and fibrosis by inhibition of the TLR4 signaling pathway in mice with chronic liver injury. Eritoran may serve as a potential drug for chronic liver disease.
| S-EPMC8235164 | biostudies-literature
Project description:Background/aimsThe sphingomyelin/ceramide signaling pathway is an important component of many cellular processes implicated in the pathogenesis of lung disease. Acid sphingomyelinase (ASM) is a key mediator of this pathway, but its specific role in pulmonary fibrosis has not been previously investigated. Here we used the bleomycin model of pulmonary fibrosis to investigate fibrotic responses in normal and ASM knockout (ASM(-/-)) mice, and in NIH3T3 fibroblasts with and without ASM siRNA treatment.MethodsMice and cells with and without ASM activity were treated with bleomycin, and the effects on lung inflammation, formation of collagen producing myofibroblasts, and apoptosis were assessed.ResultsThe development of bleomycin-induced inflammation and fibrosis in wildtype mice correlated with the rapid activation of ASM, and was markedly attenuated in the absence of ASM activity. Along with the elevated ASM activity, there also was an elevation of acid ceramidase (AC) activity, which was sustained for up to 14 days post-bleomycin treatment. Studies in NIH3T3 fibroblasts confirmed these findings, and revealed a direct effect of ASM/AC activation on the formation of myofibroblasts. Cell studies also showed that a downstream effect of bleomycin treatment was the production of sphingosine-1-phosphate.ConclusionsThese data demonstrate that the sphingomyelin/ceramide signaling pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis, and suggest that inhibition of ASM may potentially slow the fibrotic process in the lung.
| S-EPMC3048941 | biostudies-literature