scholarly journals PDCD4 deficiency ameliorates left ventricular remodeling and insulin resistance in a rat model of type 2 diabetic cardiomyopathy

2020 ◽  
Vol 8 (1) ◽  
pp. e001081
Author(s):  
Jie Zhang ◽  
Meng Zhang ◽  
Zhi Yang ◽  
Shanying Huang ◽  
Xiao Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Akt Pathway ◽  
Underlying Mechanisms

ObjectiveDiabetic cardiomyopathy (DCM) is characterized by cardiac remodeling, dysfunction, and insulin resistance; however, the underlying mechanism has not been fully elucidated. Programmed cell death 4 (PDCD4) is a novel inflammation and apoptosis gene, but its role in type 2 DCM remains elusive. We aimed to determine if PDCD4 intervention improves DCM by affecting left ventricular remodeling, function, and insulin resistance.Research design and methodsWe designed a PDCD4-/- rat, established a type 2 diabetes animal model, and constructed a PDCD4 overexpressed adenovirus and PDCD4 small interfer RNA (siRNA) vectors to alter PDCD4 expression in H9c2 cardiomyocytes. Thereafter, glucose levels, lipid metabolism, echocardiography, and extent of myocardial fibrosis, inflammation, and apoptosis were compared in vivo and in vitro.ResultsPDCD4 deficiency improved insulin resistance, cardiac remodeling, and dysfunction in type 2 DCM rats and improved myocardial hypertrophy, fibrosis, inflammation, and apoptosis. Proliferation and transformation of cardiac fibroblasts was reduced via PDCD4 downregulation in vitro under high-glucose stimulation. Furthermore, PDCD4 regulated the myocardial phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) pathway in vivo and in vitro. PDCD4 intervention affected cardiac remodeling, dysfunction, and insulin resistance by influencing fibrosis, inflammation, and apoptosis via the PI3K-AKT pathway in vivo.ConclusionsPDCD4 knockdown protected against left ventricular remodeling, dysfunction, and insulin resistance in type 2 DCM rats. The underlying mechanisms may involve reducing cardiomyocyte apoptosis, inflammation, fibrosis, and normalized PI3K-AKT phosphorylation. To the best of our knowledge, our study is the first to report the effects and underlying mechanisms of PDCD4 in type 2 DCM. These results provide a potential new treatment avenue for improving the prognosis of patients with type 2 DCM.

scholarly journals Low‐intensity Pulsed Ultrasound Ameliorates Angiotension Ii-induced Cardiac Fibrosisbyalleviating Inflammation via a Caveolin-1-dependent Pathway

2020 ◽  
Author(s):  
Kun Zhao ◽  
Jing Zhang ◽  
Tianhua Xu ◽  
Chuanxi Yang ◽  
Liqing Weng ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Pulsed Ultrasound ◽  
Caveolin 1 ◽  
Low Intensity Pulsed Ultrasound

Abstract Background: Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by Angiotensin II (AngII). Concerning the fact that low‐intensity pulsed ultrasound (LIPUS) has been reported to improve cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechanotransductionanditsdownstream pathways, we aimed to investigate whether LIPUS could also exert a protective effect on ameliorating AngII-induced cardiac hypertrophy and fibrosis andand if so, to further elucidate the underlying molecular mechanisms.Methods: In our study, we used AngII to mimic the animal and cell culture models of cardiac hypertrophy and fibrosis, where LIPUS irradiation (0.5MHz, 77.20mW/cm2) was applied for 20 minutes every 2 days from 1 week before surgery to 4 weeks after surgery in vivo, and every 6 hours for a total of 2 times in vitro. Following that, the levels of cardiac hypertrophy and fibrosis were evaluated by echocardiographic, histopathological, and molecular biological methods. Results: Our results showed that LIPUS irradiation could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-inducedrelease of inflammatory cytokines, while the protective effects were limited on cardiac hypertrophy in vitro. Given that LIPUS irradiation increased the expression of caveolin-1 related to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vitro, by which LIPUS-induced downregulation of inflammation was reversed and the anti-fibrosis effects of LIPUS irradiation were absent. Conclusions: Taken together, these results indicate that LIPUS irradiation could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeuticapparatus in clinical practice.

scholarly journals Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Yang Zhao ◽  
Huaxin Sun ◽  
Kai Li ◽  
Luxiang Shang ◽  
Xiaoyan Liang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular ◽  
H9c2 Cells ◽  
Tnf Α ◽  
Underlying Mechanisms

Background. Cholinergic anti-inflammatory pathway (CAP) is implicated in cardioprotection in chronic heart failure (CHF) by downregulating inflammation response. Mitochondrial injuries play an important role in ventricular remodeling of the CHF process. Herein, we aim to investigate whether CAP elicitation prevents ventricular remodeling in CHF by protecting myocardial mitochondrial injuries and its underlying mechanisms. Methods and Results. CHF models were established by ligation of anterior descending artery for 5 weeks. Postoperative survival rats were assigned into 5 groups: the sham group (sham, n = 10 ), CHF group (CHF, n = 11 ), Vag group (CHF+vagotomy, n = 10 ), PNU group (CHF+PNU-282987 for 4 weeks, n = 11 ), and Vag+PNU group (CHF+vagotomy+PNU-282987 for 4 weeks, n = 10 ). The antiventricular remodeling effect of cholinergic elicitation was evaluated in vivo, and H9C2 cells were selected for the TNF-α gradient stimulation experiment in vitro. In vivo, CAP agitated by PNU-282987 alleviated the left ventricular dysfunction and inhibited the energy metabolism remodeling. Further, cholinergic elicitation increased myocardium ATP levels and reduced systemic inflammation. CAP induction alleviates macrophage infiltration and cardiac fibrosis, of which the effect is counteracted by vagotomy. Myocardial mitochondrial injuries were ameliorated by CAP activation, including the reserved ultrastructural integrity, declining ROS overload, reduced myocardial apoptosis, and enhanced mitochondrial fusion. In vitro, TNF-α intervention significantly exacerbated the mitochondrial damage in H9C2 cells. Conclusion. CAP elicitation effectively improves ischemic ventricular remodeling by suppressing systemic and cardiac inflammatory response, attenuating cardiac fibrosis and potentially alleviating the mitochondrial dysfunction linked to hyperinflammation reaction.

scholarly journals The miRNA199a/SIRT1/P300/Yy1/sST2 signaling axis regulates adverse cardiac remodeling following MI

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Carmen Asensio-Lopez ◽  
Yassine Sassi ◽  
Fernando Soler ◽  
Maria Josefa Fernandez del Palacio ◽  
Domingo Pascual-Figal ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Specific Treatment ◽  
Left Ventricular ◽  
Acute Stage ◽  
Soluble St2 ◽  
Underlying Mechanisms

AbstractLeft ventricular remodeling following myocardial infarction (MI) is related to adverse outcome. It has been shown that an up-regulation of plasma soluble ST2 (sST2) levels are associated with lower pre-discharge left ventricular (LV) ejection fraction, adverse cardiovascular outcomes and mortality outcome after MI. The mechanisms involved in its modulation are unknown and there is not specific treatment capable of lowering plasma sST2 levels in acute-stage HF. We recently identified Yin-yang 1 (Yy1) as a transcription factor related to circulating soluble ST2 isoform (sST2) expression in infarcted myocardium. However, the underlying mechanisms involved in this process have not been thoroughly elucidated. This study aimed to evaluate the pathophysiological implication of miR-199a-5p in cardiac remodeling and the expression of the soluble ST2 isoform. Myocardial infarction (MI) was induced by permanent ligation of the left anterior coronary artery in C57BL6/J mice that randomly received antimiR199a therapy, antimiR-Ctrl or saline. A model of biomechanical stretching was also used to characterize the underlying mechanisms involved in the activation of Yy1/sST2 axis. Our results show that the significant upregulation of miR-199a-5p after myocardial infarction increases pathological cardiac hypertrophy by upregulating circulating soluble sST2 levels. AntimiR199a therapy up-regulates Sirt1 and inactivates the co-activator P300 protein, thus leading to Yy1 inhibition which decreases both expression and release of circulating sST2 by cardiomyocytes after myocardial infarction. Pharmacological inhibition of miR-199a rescues cardiac hypertrophy and heart failure in mice, offering a potential therapeutic approach for cardiac failure.

scholarly journals Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2545
Author(s):  
Ya-Hui Chen ◽  
Po-Hui Wang ◽  
Pei-Ni Chen ◽  
Shun-Fa Yang ◽  
Yi-Hsuan Hsiao
Keyword(s):  
Cervical Cancer ◽  
Potential Role ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Anticancer Effects ◽  
Clinical Benefits ◽  
Underlying Mechanisms

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

scholarly journals Antidiabetic Properties of Naringenin: A Citrus Fruit Polyphenol

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 99 ◽  
Author(s):  
Danja J. Den Hartogh ◽  
Evangelia Tsiani
Keyword(s):  
Insulin Resistance ◽  
Animal Studies ◽  
Citrus Fruit ◽  
Epidemiological Studies ◽  
Personal Health ◽  
Current Review ◽  
Vegetables And Fruits

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and hyperglycemia and is associated with personal health and global economic burdens. Current strategies/approaches of insulin resistance and T2DM prevention and treatment are lacking in efficacy resulting in the need for new preventative and targeted therapies. In recent years, epidemiological studies have suggested that diets rich in vegetables and fruits are associated with health benefits including protection against insulin resistance and T2DM. Naringenin, a citrus flavanone, has been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, immunomodulatory and antidiabetic properties. The current review summarizes the existing in vitro and in vivo animal studies examining the anti-diabetic effects of naringenin.

Abstract 2523: Azelnidipine Enhances Beneficial Effects of Olmesartan on Left Ventricular Remodeling During the Development of Hypertension-induced Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xian Wu Cheng ◽  
Kenji Okumura ◽  
Kohzo Nagata ◽  
Aiko Inoue ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nadph Oxidase ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Oxidase Inhibitor ◽  
List Type ◽  
Superoxide Anion Production ◽  
Cardioprotective Effects

Objective: This work was undertaken to investigate the comparative effect of angiotensin II type 1 receptor blocker (ARB) and a combination of ARB and calcium channel blocker (CCB) on left ventricular (LV) remodeling during the development of hypertensive heart failure (H-HF). Methods and Results: We treated 8% salt-loaded Dahl salt-sensitive hypertensive rats (n = 10 for each group) with vehicle, hydralazine (5 mg/kg/d), olmesartan (OLM, 5 mg/kg/d), or combined OLM and azelnidipine (AZE, 2mg/kg/d) for 8 weeks. The rats fed 0.3% salt served as age-matched controls. The abundance of Cat mRNAs and proteins were localized in cardiac myocytes (CMCs), and Cat-dependent activities were increased by 4.1-fold in the LV of H-HF rats (n = 8, P< 0.001) and were reduced by OLM treatment. OLM suppressed the elastic lamina degradation concomitant with decreased local Cat S expression in intracoronary smooth muscle cells (SMCs) and restored the balance of elastin to collagen in the LV tissue of H-HF rats (H-HF 4.6 ± 0.9% vs. OLM 15.5 ± 2.1% elastin content/collagen content (%), n = 6, P< 0.0±1; control 22±2.1%). OLM suppressed not only macrophage infiltration but also levels of NADPH oxidase components (p22 phox , gp91 phox , and p47 phox ) concomitant with decreased NADPH activity and O2- production in LV tissues of H-HF rats. Along with its comparable anti-inflammatory effect, add-on AZE further improved all of these parameter changes by OLM. Furthermore, combination therapy significantly enhanced the improvement of LV fibrosis, hypertrophy, stiffness, and dysfunction by OLM. In vitro, H 2 O 2 stimulated Cat S mRNA and protein expression and activity, and these increases were abolished by pretreatment with the antioxidants such as MnTmPyp (50 μmol/L) and N-acetylcysteine (5 mmol/L) as well as a NADPH oxidase inhibitor apocynin (100 μmol/L) in culture CMCs, SMCs, and macrophages (n = 6, P< 0.01). Conclusions: OLM and a combination of OLM and AZE exerted cardioprotective effects in hypertensive HF, via elastolytic Cat activation inhibition by the reduction of NADPH oxidase-dependent superoxide anion production. AZE enhanced the cardioprotective effects of OLM. Thus, the combination of ARB with CBB is a promising potential therapeutic strategy for H-HF.

scholarly journals Antidiabetic Effects of Hydroxytyrosol: In Vitro and In Vivo Evidence

Antioxidants ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 188 ◽  
Author(s):  
Filip Vlavcheski ◽  
Mariah Young ◽  
Evangelia Tsiani
Keyword(s):  
Insulin Resistance ◽  
Pathological Condition ◽  
Current Treatment ◽  
In Vivo Studies ◽  
Olive Leaves ◽  
Treatment And Prevention ◽  
Antidiabetic Effects

Insulin resistance, a pathological condition characterized by defects in insulin action leads to the development of Type 2 diabetes mellitus (T2DM), a disease which is currently on the rise that pose an enormous economic burden to healthcare systems worldwide. The current treatment and prevention strategies are considerably lacking in number and efficacy and therefore new targeted therapies and preventative strategies are urgently needed. Plant-derived chemicals such as metformin, derived from the French lilac, have been used to treat/manage insulin resistance and T2DM. Other plant-derived chemicals which are not yet discovered, may have superior properties to prevent and manage T2DM and thus research into this area is highly justifiable. Hydroxytyrosol is a phenolic phytochemical found in olive leaves and olive oil reported to have antioxidant, anti-inflammatory, anticancer and antidiabetic properties. The present review summarizes the current in vitro and in vivo studies examining the antidiabetic properties of hydroxytyrosol and investigating the mechanisms of its action.

scholarly journals Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure

2019 ◽  
Vol 5 (1) ◽  
pp. 22 ◽  
Author(s):  
Henri Charrier ◽  
Marie Cuvelliez ◽  
Emilie Dubois-Deruy ◽  
Paul Mulder ◽  
Vincent Richard ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systems Biology ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mirna Signature ◽  
Artery Ligation ◽  
Proteomic Data

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

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