Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension.
Ontology highlight
ABSTRACT:
SUBMITTER: Song L
PROVIDER: S-EPMC7695461 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
Publications
Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension.
Song LouJin L Chen Xian X Swanson Terri A TA LaViolette Brianna B Pang Jincheng J Cunio Teresa T Nagle Michael W MW Asano Shoh S Hales Katherine K Shipstone Arun A Sobon Hanna H Al-Harthy Sabra D SD Ahn Youngwook Y Kreuser Steven S Robertson Andrew A Ritenour Casey C Voigt Frank F Boucher Magalie M Sun Furong F Sessa William C WC Roth Flach Rachel J RJ
eLife 20201117
The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little is known about its role in chronic cardiac dysfunction. Here, we demonstrate that angiotensin II infusion induced cardiac inflammation and fibrosis at 1 week and caused cardiac dysfunction and impaired lymphatic transport at 6 weeks in mice, while co-administration of VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis in distinct cell ...[more]
Similar Datasets
Project description:Obesity rates have rapidly increased worldwide and obesity-related diseases such as hypertension and cardiovascular diseases have become leading factors for global morbidity and mortality. Currently, there are no effective treatments that can prevent or reverse obesity long-term, and hence the prevention of obesity-related adverse effects such as hypertension is critical. Qingda granule (QDG) is a condensed Traditional Chinese Medicine (TCM) formula that has been used clinically for treating hypertension, however, its effectiveness in obesity-induced hypertension and cardiac dysfunction remains explored. Mouse models of obesity via long-term feeding of high-fat high-fructose diet (HFFD) were established to examine the effect and mechanism of QDG in protecting against obesity-induced hypertension and cardiac dysfunction. C57BL/6 mice were fed with either normal diet or HFFD over a period of 16 weeks and administered with either saline or QDG for assessment of obesity-induced blood pressure and cardiac function. QDG administration demonstrated robust anti-hypertensive effects and significantly attenuated HFFD-induced elevations in blood pressures. Moreover, QDG treatment also demonstrated robust cardioprotective effects during obesity-induced hypertension by markedly improving cardiac function and preventing cardiac hypertrophy. QDG protected against obesity-induced hypertension and cardiac dysfunction was due to its ability to prevent adverse chronic activation of Akt signaling pathway during long-term feeding of HFFD. Long-term usage of QDG treatments exhibited no observable side effects and also completely prevented obesity-induced organ damage, demonstrating the feasibility and safety of prolonged use. Our findings thus elucidated the role of QDG in preventing obesity-induced hypertension and cardiac hypertrophy via inhibiting adverse activation of Akt signaling activation. Therefore, our study provides the theoretical basis for the utilization of QDG as both a safe and effective drug in the therapeutic treatment of metabolic diseases such as obesity-induced hypertension.
| S-EPMC9791312 | biostudies-literature
Project description:The excessive inflammation triggered by damage-associated molecular patterns (DAMPs) after myocardial infarction (MI) is responsible for the development of cardiac dysfunction and adverse remodeling, while the mechanisms by which inflammation is fine tuned remain to be fully elucidated. MicroRNA-21 (miR-21) has been shown to function in cardiovascular diseases, while its role in inflammatory responses and cardiac function post MI in mice remains unknown. Here, we found that miR-21 expression was markedly increased in border and infarct areas of cardiac tissues during the early inflammatory phase of MI model established by ligating the left-anterior descending coronary artery. MiR-21 knockout mice had decreased survival rates, worse cardiac dysfunction, and increased infarct and scar areas after MI compared with WT mice. MiR-21 knockout mice showed significantly higher levels of inflammatory cytokines including IL-1β, IL-6, and TNF-α in cardiac tissues, as well as infiltration of CD11b+ monocytes/macrophages with higher expression level of inflammatory cytokines. MI induced the great release of high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60) in cardiac tissue. MiR-21 deficiency significantly promoted the inflammatory cytokine production triggered by DAMPs in macrophages, whereas, miR-21 overexpression markedly inhibited the inflammatory cytokine production. Mechanistically, miR-21 deficiency enhanced p38 and NF-κB signaling activation in cardiac tissue post MI and macrophages treated with DAMPs. MiR-21 was found to directly target kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), which promoted DAMP-triggered inflammatory responses in macrophages. Furthermore, KBTBD7 interacted with MKK3/6 and promoted their activation, which in turn enhanced the activation of downstream p38 and NF-κB signaling induced by DAMPs. Therefore, our findings demonstrate that miR-21 attenuates inflammation, cardiac dysfunction, and maladaptive remodeling post MI through targeting KBTBD7 and inhibiting p38 and NF-κB signaling activation, suggesting that miR-21 may function as a novel potential therapeutic target for MI.
| S-EPMC6039462 | biostudies-literature
Project description:Doxorubicin (DOX) is known as an effective drug in the fight against various cancers. However, one of the greatest impediments is DOX-induced cardiomyopathy, which may potentially lead to heart failure. Accumulating evidence has shed light on the pathological mechanism of DOX-induced cardiotoxicity, but treatments to mitigate the cardiac damage are still required. In an attempt to address this issue, we evaluated whether exercise provides cardioprotective effects on the DOX-induced cardiotoxicity. We showed that treadmill exercise (3 times/week; 1-week of exercise acclimatization and 4-weeks of endurance exercise) during the DOX treatment successfully prevented the cardiac dysfunction. The DOX-stimulated expression of I?B?, NF-?B, COX-2, and IL-8 were all downregulated by exercise as well as the fibrosis factors (TGF-?1, phosphorylated ERK, Sp1, and CTGF). Moreover, we showed that treadmill exercise diminished the expression of several cardiac remodeling-associated factors, such as FGF2, uPA, MMP2, and MMP9. These results were in line with the finding that exercise intervention reduced cardiac fibrosis and restored cardiac function, with higher values of ejection fraction and fractional shortening compared to the DOX-treated group. Two commonly used indicators of cardiac injury, lactate dehydrogenase, and creatine kinase-MB, were also decreased in the exercise group. Collectively, our results suggested that it may be beneficial to prescribe treadmill exercise as an adjunct therapy to limit cardiac damage caused by DOX.
| S-EPMC7281105 | biostudies-literature
Project description:AimsClinical studies suggest that intake of omega-3 polyunsaturated fatty acids (omega-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with omega-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between omega-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [alpha-linolenic acid (ALA)].Methods and resultsWe assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with omega-3 PUFA over a dose range that spanned the intake of humans taking omega-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = -0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B(2) and serum tumour necrosis factor-alpha.ConclusionDietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.
| S-EPMC2721645 | biostudies-literature
Project description:To explore the effects of celecoxib on pressure overload-induced cardiac hypertrophy (CH), cardiac dysfunction and explore the possible protective mechanisms. We surgically created abdominal aortic constrictions (AAC) in rats to induce CH. Rats with CH symptoms at 4 weeks after surgery were treated with celecoxib [2 mg/100 g body-weight(BW)] daily for either 2 or 4 weeks. Survival rate, blood pressure and cardiac function were evaluated after celecoxib treatment. Animals were killed, and cardiac tissue was examined for morphological changes, cardiomyocyte apoptosis, fibrosis, inflammation and oxidative stress. Four weeks after AAC, rats had significantly higher systolic, diastolic and mean blood pressure, greater heart weight and enlarged cardiomyocytes, which were associated with cardiac dysfunction. Thus, the CH model was successfully established. Two weeks later, animals had impaired cardiac function and histopathological abnormalities including enlarged cardiomyocytes and cardiac fibrosis, which were exacerbated 2 weeks later. However, these pathological changes were remarkably prevented by the treatment of celecoxib, independent of preventing hypertension. Mechanistic studies revealed that celecoxib-induced cardiac protection against CH and cardiac dysfunction was due to inhibition of apoptosis via the murine double mimute 2/P53 pathway, inhibition of inflammation via the AKT/mTOR/NF-κB pathway and inhibition of oxidative stress via increases in nuclear factor E2-related factor-2-mediated gene expression of multiple antioxidants. Celecoxib suppresses pressure overload-induced CH by reducing apoptosis, inflammation and oxidative stress.
| S-EPMC4717861 | biostudies-other
Project description:Arterial hypertension causes left ventricular hypertrophy leading to dilated cardiomyopathy. Following compensatory cardiomyocyte hypertrophy, cardiac dysfunction develops due to loss of cardiomyocytes preceded or paralleled by cardiac fibrosis. Zyxin acts as a mechanotransducer in vascular cells that may promote cardiomyocyte survival. Here, we analyzed cardiac function during experimental hypertension in zyxin knockout (KO) mice. In zyxin KO mice, made hypertensive by way of deoxycorticosterone acetate (DOCA)-salt treatment telemetry recording showed an attenuated rise in systolic blood pressure. Echocardiography indicated a systolic dysfunction, and isolated working heart measurements showed a decrease in systolic elastance. Hearts from hypertensive zyxin KO mice revealed increased apoptosis, fibrosis and an upregulation of active focal adhesion kinase as well as of integrins α5 and β1. Both interstitial and perivascular fibrosis were even more pronounced in zyxin KO mice exposed to angiotensin II instead of DOCA-salt. Stretched microvascular endothelial cells may release collagen 1α2 and TGF-β, which is characteristic for the transition to an intermediate mesenchymal phenotype, and thus spur the transformation of cardiac fibroblasts to myofibroblasts resulting in excessive scar tissue formation in the heart of hypertensive zyxin KO mice. While zyxin KO mice per se do not reveal a cardiac phenotype, this is unmasked upon induction of hypertension and owing to enhanced cardiomyocyte apoptosis and excessive fibrosis causes cardiac dysfunction. Zyxin may thus be important for the maintenance of cardiac function in spite of hypertension.
| S-EPMC8786748 | biostudies-literature
Project description:Background and purposeHypertension is a multifactorial disease, manifested by vascular dysfunction, increased superoxide production, and perivascular inflammation. In this study, we have hypothesized that 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG) would inhibit vascular inflammation and protect from vascular dysfunction in an experimental model of hypertension.Experimental approachPGG was administered to mice every 2 days at a dose of 10 mg·kg-1 i.p during 14 days of Ang II infusion. It was used at a final concentration of 20 μM for in vitro studies in cultured cells.Key resultsAng II administration increased leukocyte and T-cell content in perivascular adipose tissue (pVAT), and administration of PGG significantly decreased total leukocyte and T-cell infiltration in pVAT. This effect was observed in relation to all T-cell subsets. PGG also decreased the content of T-cells bearing CD25, CCR5, and CD44 receptors and the expression of both monocyte chemoattractant protein 1 (CCL2) in aorta and RANTES (CCL5) in pVAT. PGG administration decreased the content of TNF+ and IFN-γ+ CD8 T-cells and IL-17A+ CD4+ and CD3+ CD4- CD8- cells. Importantly, these effects of PGG were associated with improved vascular function and decreased ROS production in the aortas of Ang II-infused animals independently of the BP increase. Mechanistically, PGG (20 μM) directly inhibited CD25 and CCR5 expression in cultured T-cells. It also decreased the content of IFN-γ+ CD8+ and CD3+ CD4- CD8- cells and IL-17A+ CD3+ CD4- CD8- cells.Conclusion and implicationPGG may constitute an interesting immunomodulating strategy in the regulation of vascular dysfunction and hypertension.Linked articlesThis article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.
| S-EPMC6534792 | biostudies-literature
Project description:RationaleSepsis produces significant mitochondrial and contractile dysfunction in the heart, but the role of superoxide-derived free radicals in the genesis of these abnormalities is not completely understood.ObjectivesThe study was designed to test the hypothesis that superoxide scavenger administration prevents endotoxin-induced cardiac mitochondrial and contractile dysfunction.MethodsFour groups of rats were studied, and animals were injected with either saline, endotoxin, endotoxin plus polyethylene glycol-adsorbed-superoxide dismutase (PEG-SOD; a free-radical scavenger), or PEG-SOD alone. Animals were killed 48 h after injections. We then measured cardiac mitochondrial generation of reactive oxygen species (ROS), formation of free-radical reaction products (protein carbonyls, lipid aldehydes, nitrotyrosine), mitochondrial function, and cardiac contractile function.Measurements and main resultsEndotoxin elicited increases in cardiac mitochondrial ROS formation (p < 0.001), increases in cardiac levels of free-radical reaction products, reductions in mitochondrial ATP generation (p < 0.001), and decrements in cardiac pressure-generating capacity (p < 0.01). Administration of PEG-SOD blocked formation of free-radical reaction products, prevented mitochondrial dysfunction, and preserved cardiac contractility. For example, mitochondrial ATP generation was 923 +/- 50, 392 +/- 32, 753 +/- 25, and 763 +/- 36 nmol/min/mg, respectively, for control, endotoxin, endotoxin + PEG-SOD, and PEG-SOD groups (p < 0.001). In addition, cardiac systolic pressure generation at a diastolic pressure of 15 mm Hg averaged 110 +/- 11, 66 +/- 7, 129 +/- 10 and 124 +/- 5 mm Hg, respectively, for control, endotoxin, endotoxin + PEG-SOD, and PEG-SOD groups (p < 0.01).ConclusionThese data indicate that superoxide-derived oxidants play a critical role in the development of cardiac mitochondrial and contractile dysfunction in endotoxin-induced sepsis.
| S-EPMC2662969 | biostudies-literature
Project description:Background Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin-like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin-like molecules can directly cause PH-associated cardiac dysfunction and remodeling. Methods and Results In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin-like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac-specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca2+ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP-activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage-associated molecular pattern molecule high-mobility group box 1, and subsequently induced pro-proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti-Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Conclusions Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH-associated RV hypertrophy and failure in humans.
| S-EPMC10111547 | biostudies-literature
Project description:Background Cardiac fibrosis is characterized by excessive extracellular matrix deposition that contributes to compromised cardiac function and potentially heart failure. Disruptor of telomeric silencing 1-like (Dot1L) is the catalytic enzyme required for histone H3K79 methylation which has been demonstrated to play a role in transcriptional activation. However, the functions of Dot1L in the process of cardiac fibrosis still remain unknown. Results In the present study, we found that endogenous Dot1L is upregulated in cardiac fibroblasts (CFs) treated with angiotensin II (Ang II) or transforming growth factor (TGF)-β1, along with elevated extracellular matrix (ECM) such as fibronectin, collagen I and III. Silencing or inhibiting Dot1L mitigated Ang II-induced myofibroblast generation and fibrogenesis. We identified the transcription factor-forkhead box O (FoxO) 3a as a novel substrate of Dot1L, the transcriptional activating mark H3K79me3 level on the promoter of FoxO3a was increase in activated-CFs, and inhibition of Dot1L markedly decreased FoxO3a transcription accompanied by a significant decrease in the expression of fibrogenic gene. Knockdown of FoxO3a could alleviate ECM deposition induced by Ang II, on the contrary, overexpression FoxO3a resulting in CFs activation. Consistently, in vivo Dot1L ablation rescued myocardial ischemia-induced cardiac fibrosis and improved cardiac function. Conclusions Our findings conclude that upregulation of Dot1L results in activation of the cardiac fibroblasts to promote profibrotic gene, eventually causes cardiac fibrosis. Pharmacological targeting for Dot1L might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00877-5.
| S-EPMC9392317 | biostudies-literature