Aminoacylase-1 plays a key role in myocardial fibrosis and the therapeutic effects of 20(S)-ginsenoside Rg3 in mouse heart failure

Myocardial fibrosis represents the primary pathological change associated with diabetic cardiomyopathy and heart failure, and it leads to decreased myocardial compliance with impaired cardiac diastolic and systolic function. Quercetin, an active ingredient in various medicinal plants, exerts therapeutic effects against cardiovascular diseases. Here, we investigate whether SIRT5- and IDH2-related desuccinylation is involved in the underlying mechanism of myocardial fibrosis in heart failure while exploring related therapeutic drugs for mitochondrial quality surveillance. Mouse models of myocardial fibrosis and heart failure, established by transverse aortic constriction (TAC), were administered with quercetin (50 mg/kg) daily for 4 weeks. HL-1 cells were pretreated with quercetin and treated with high glucose (30 mM) in vitro. Cardiac function, western blotting, quantitative PCR, enzyme-linked immunosorbent assay, and immunofluorescence analysis were employed to analyze mitochondrial quality surveillance, oxidative stress, and inflammatory response in myocardial cells, whereas IDH2 succinylation levels were detected using immunoprecipitation. Myocardial fibrosis and heart failure incidence increased after TAC, with abnormal cardiac ejection function. Following high-glucose treatment, HL-1 cell activity was inhibited, causing excess production of reactive oxygen species and inhibition of mitochondrial respiratory complex I/III activity and mitochondrial antioxidant enzyme activity, as well as increased oxidative stress and inflammatory response, imbalanced mitochondrial quality surveillance and homeostasis, and increased apoptosis. Quercetin inhibited myocardial fibrosis and improved cardiac function by increasing mitochondrial energy metabolism and regulating mitochondrial fusion/fission and mitochondrial biosynthesis while inhibiting the inflammatory response and oxidative stress injury. Additionally, TAC inhibited SIRT5 expression at the mitochondrial level and increased IDH2 succinylation. However, quercetin promoted the desuccinylation of IDH2 by increasing SIRT5 expression. Moreover, treatment with si-SIRT5 abolished the protective effect of quercetin on cell viability. Hence, quercetin may promote the desuccinylation of IDH2 through SIRT5, maintain mitochondrial homeostasis, protect mouse cardiomyocytes under inflammatory conditions, and improve myocardial fibrosis, thereby reducing the incidence of heart failure.

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60 Myocardial fibrosis and heart failure

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(04)90039-2 ◽

2004 ◽

Vol 3 (1) ◽

pp. 13

Author(s):

M JIMENEZNAVARRO

Keyword(s):

Heart Failure ◽

Myocardial Fibrosis

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Pharmacology of Ivabradine and the Effect on Chronic Heart Failure

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190809093144 ◽

2019 ◽

Vol 19 (21) ◽

pp. 1878-1901 ◽

Cited By ~ 3

Author(s):

Yue Zhou ◽

Jian Wang ◽

Zhuo Meng ◽

Shuang Zhou ◽

Jiayu Peng ◽

...

Keyword(s):

Heart Failure ◽

Heart Rate ◽

Chronic Heart Failure ◽

Underlying Mechanism ◽

Clinical Syndrome ◽

Hcn Channels ◽

Therapeutic Effects ◽

Diastolic Depolarization ◽

High Incidence ◽

Spontaneous Phase

Chronic Heart Failure (CHF) is a complex clinical syndrome with a high incidence worldwide. Although various types of pharmacological and device therapies are available for CHF, the prognosis is not ideal, for which, the control of increased Heart Rate (HR) is critical. Recently, a bradycardic agent, ivabradine, is found to reduce HR by inhibiting the funny current (If). The underlying mechanism states that ivabradine can enter the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and bind to the intracellular side, subsequently inhibiting the If. This phenomenon can prolong the slow spontaneous phase in the diastolic depolarization, and thus, reduce HR. The clinical trials demonstrated the significant effects of the drug on reducing HR and improving the symptoms of CHF with fewer adverse effects. This review primarily introduces the chemical features and pharmacological characteristics of ivabradine and the mechanism of treating CHF. Also, some expected therapeutic effects on different diseases were also concluded. However, ivabradine, as a typical If channel inhibitor, necessitates additional research to verify its pharmacological functions.

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Therapeutic effects of medicinal plants on isoproterenol-induced heart failure in rats

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.111101 ◽

2021 ◽

Vol 134 ◽

pp. 111101

Author(s):

Faeze Keihanian ◽

Mohsen Moohebati ◽

Amin Saeidinia ◽

Seyed Ahmad Mohajeri ◽

Saeid Madaeni

Keyword(s):

Heart Failure ◽

Medicinal Plants ◽

Therapeutic Effects

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The link between left ventricular extracellular volume determined by T1 myocardial mapping and gut microbiota composition in individuals with heart failure and preserved ejection fraction

European Heart Journal ◽

10.1093/ehjci/ehaa946.0864 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A.N Kaburova ◽

O.M Drapkina ◽

S.M Uydin ◽

M.V Vishnyakova ◽

M.S Pokrovskaya ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Gut Microbiota ◽

Myocardial Fibrosis ◽

Volume Fraction ◽

Extracellular Volume ◽

Left Ventricular ◽

Diffuse Myocardial Fibrosis ◽

Rrna Gene ◽

Preserved Ejection Fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) represents a major challenge in modern cardiology. As described previously, in HFpEF comorbidities promote a systemic inflammatory state, leading to diffuse myocardial fibrosis resulting in myocardial stiffening. Gut dysbiosis which is considered as the novel source of chronic systemic inflammation has been actively investigated as the risk factor for the development and aggravation of cardiovascular diseases including heart failure. Cardiac magnetic resonance T1-mapping is a novel tool, which allows noninvasive quantification of the extracellular space and diffuse myocardial fibrosis. Moreover, the extracellular volume (ECV) fraction can be calculated, providing information on the relative expansion of the extracellular matrix, thus being a noninvasive alternative to myocardial biopsy studies. Purpose The research was aimed at investigating the correlation between the left ventricular ECV and gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index <35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide >125 pg/ml and symptoms of heart failure). The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. As the last step of research T1-myocardial mapping with the modified look-locker inversion-recovery protocol (MOLLI) sequence at 1.5 Tesla was performed to assess left ventricular extracellular volume fraction. Results The mean±std in ECV was 31.02±4.4%. The relative abundance (%) of the most prevalent phyla in gut microbiota was 48±22.5 for Firmicutes, 47.4±22.8 for Bacteroidetes and 1.5 [1.5; 2.5] for Proteobacteria. The analysis showed significant negative correlations between ECV and the following bacterial genera: Faecalibacterium (r=−0.35), Blautia (r=−0.43), Lachnoclostridium (r=−0.32). Moreover ECV positively correlated with Holdemania (r=0.4), Victivallis (r=0.38), Dehalobacterium (r=0.38), Enterococcus (r=0.33) and Catabacter (r=0.32). All correlation values with p<0.05. Conclusion We discovered both negative and positive significant correlations between ECV – the non-invasive marker of myocardial fibrosis and several bacterial genera, which may have negative impact on myocardial remodeling in HF-pEF. Funding Acknowledgement Type of funding source: None

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A novel treatment for heart failure targets myocardial fibrosis

Nature Medicine ◽

10.1038/s41591-021-01457-9 ◽

2021 ◽

Author(s):

John G. F. Cleland ◽

Pierpaolo Pellicori ◽

Arantxa González

Keyword(s):

Heart Failure ◽

Myocardial Fibrosis ◽

Novel Treatment

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The relationship between the key markers of myocardial fibrosis and gut microbiota composition in patients with heart failure and preserved ejection fraction

European Heart Journal ◽

10.1093/ehjci/ehaa946.0861 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A.N Kaburova ◽

O.M Drapkina ◽

S.M Uydin ◽

M.S Pokrovskaya ◽

S.N Koretsky ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Gut Microbiota ◽

Myocardial Fibrosis ◽

Interquartile Range ◽

Enzyme Linked Immunosorbent Assay ◽

Type I ◽

Microbiota Composition ◽

Preserved Ejection Fraction ◽

Gut Microbiota Composition

Abstract Background Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The current gold standard for the diagnosis and assessment of myocardial fibrosis is endomyocardial biopsy. A number of circulating biomarkers have been proposed for the assessment of myocardial fibrosis, however the most consistent results have been found for C-terminal propeptide of procollagen type I (PICP) and N-terminal propeptide of pro-collagen type III (PIIINP). Some evidence suggests the possible link between the gut microbiota composition and myocardioal fibrosis. Purpose The aim of the study was to investigate the association between the serum markers of myocardial fibrosis (PICP and PIIINP) with gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index <35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide >125 pg/ml and symptoms of HF). The levels of PICP and PIIINP were evaluated in patients' serum using enzyme-linked immunosorbent assay. The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. Results The mediana and interquartile range in PICP was 918 [700; 1044] pg/ml, in PIIINP it was 6.215 [3.99; 8.29] pg/ml. The analysis revealed significant correlations between PICP and the following bacterial genera of Firmicutes:Ruminococcus (r=−0,36); Gemmiger (r=−0,35), Allisonella (r=0,32) and Howardella (r=−0,30). PIIINP significantly correlated with 2 genera: Blautia which belongs to Firmicutes phylum (r=0,36) and Bilophila which belongs to Proteobacteria phylum (r=−0,33). All values with p<0,05. Conclusion Both PICP and PIIINP had negative significant correlations with beneficial bacterial genera and positive correlations with several potencially harmful gut bacterial genera. This type of relationship might become the novel field of research in the group of patients with HF-pEF due to myocardial fibrosis. Funding Acknowledgement Type of funding source: None

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Synthesis and Evaluation of Heteroaryl-Substituted Dihydronaphthalenes and Indenes: Potent and Selective Inhibitors of Aldosterone Synthase (CYP11B2) for the Treatment of Congestive Heart Failure and Myocardial Fibrosis

Journal of Medicinal Chemistry ◽

10.1021/jm060055x ◽

2006 ◽

Vol 49 (7) ◽

pp. 2222-2231 ◽

Cited By ~ 69

Author(s):

Marieke Voets ◽

Iris Antes ◽

Christiane Scherer ◽

Ursula Müller-Vieira ◽

Klaus Biemel ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Myocardial Fibrosis ◽

Selective Inhibitors ◽

Aldosterone Synthase

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QSYQ Attenuates Oxidative Stress and Apoptosis Induced Heart Remodeling Rats through Different Subtypes of NADPH-Oxidase

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/824960 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Yong Wang ◽

Chun Li ◽

Yuli Ouyang ◽

Tianjiao Shi ◽

Xiaomin Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Nadph Oxidase ◽

Caspase 3 ◽

Ventricular Remodeling ◽

Cardiac Injury ◽

Myocardial Tissue ◽

Therapeutic Effects ◽

Histological Changes ◽

Nadph Oxidase 4

We aim to investigate the therapeutic effects of QSYQ, a drug of heart failure (HF) in clinical practice in China, on a rat heart failure (HF) model. 3 groups were divided: HF model group (LAD ligation), QSYQ group (LAD ligation and treated with QSYQ), and sham-operated group. After 4 weeks, rats were sacrificed for cardiac injury measurements. Rats with HF showed obvious histological changes including necrosis and inflammation foci, elevated ventricular remodeling markers levels(matrix metalloproteinases-2, MMP-2), deregulated ejection fraction (EF) value, increased formation of oxidative stress (Malondialdehyde, MDA), and up-regulated levels of apoptotic cells (caspase-3, p53 and tunnel) in myocardial tissue. Treatment of QSYQ improved cardiac remodeling through counter-acting those events. The improvement of QSYQ was accompanied with a restoration of NADPH oxidase 4 (NOX4) and NADPH oxidase 2 (NOX2) pathways in different patterns. Administration of QSYQ could attenuate LAD-induced HF, and AngII-NOX2-ROS-MMPs pathway seemed to be the critical potential targets for QSYQ to reduce the remodeling. Moreover, NOX4 was another key targets to inhibit the p53 and Caspase3, thus to reduce the hypertrophy and apoptosis, and eventually provide a synergetic cardiac protective effect.

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