Cilostazol ameliorates heart failure with preserved ejection fraction and diastolic dysfunction in obese and non-obese hypertensive mice

Reddy, Sukka Santosh; Agarwal, Heena; Barthwal, Manoj Kumar

doi:10.1016/j.yjmcc.2018.08.017

Cited by 29 publications

(18 citation statements)

References 79 publications

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“…In fact, increased monocyte activation could be observed in various stages of MI. Moreover, exaggerated inflammation, tissue damage and apoptosis are usually associated with increased visible monocyte/macrophage infiltrates in the damaged myocardium [27]. In the present study, we found that puerarin-V significantly reduced the incursion of macrophages (CD68 + cells) into the myocardium of MI mice.…”

Section: Discussionsupporting

confidence: 65%

Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Yuan

Chen

et al. 2018

Molecules

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Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic.

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Section: Discussionsupporting

confidence: 65%

Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Yuan

Chen

et al. 2018

Molecules

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“…Inflammation plays an important role in the pathophysiological process of HFpEF. In the present study, increased infiltration of macrophages and IL‐1β release were found in the ventricle of mice with HFpEF, which was in line with previous reports (Ter Maaten et al., 2016; Reddy et al, 2018). Previous studies demonstrated that MD1 serves as a negative inflammatory regulator and participates in several cardiac pathological processes (Shuai et al., 2019b; Xiong et al., 2017); therefore, we tested whether MD1 ‐KO enhanced the HFpEF‐induced inflammatory response.…”

Section: Discussionsupporting

confidence: 93%

Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation

Yang

Kong

Shuai

et al. 2020

Experimental Physiology

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Sympathetic hyperactivity can promote malignant ventricular arrhythmia (VA), and myeloid differentiation 1 (MD1) has been reported to play an important role in obesity-induced VA.However, it is not known whether an interaction of MD1 with sympathetic hyperactivity contributes to the VA induced by heart failure with preserved ejection fraction (HFpEF). The aim of this study was to investigate the potential interaction between MD1 and sympathetic hyperactivity in HFpEF-induced VA and the underlying mechanism. Eight-week-old MD1knockout (MD1-KO) and wild-type (WT) mice were subjected to a model of HFpEF induced by uninephrectomy, a continuous saline or d-aldosterone infusion and provision of drinking water containing 1.0% sodium chloride for 4 weeks. Echocardiography and haemodynamics were used to verify the model of HFpEF. An isolated electrophysiological study was performed to assess the susceptibility to VA. Four weeks later, the mice with HFpEF showed an increased heart weight to tibia length ratio, decreased left ventricular minimum rates of pressure rise (dP/dt min ), increased , lung weight to tibia length ratio and preserved left ventricular ejection fraction compared with WT mice. The mice with HFpEF exhibited increased susceptibility to VA, as shown by the shortened effective refractory period, prolonged action potential duration (APD), increased APD alternans threshold and higher incidence of VA. Moreover, we also found that mice with HFpEF showed impaired heart rate variability, sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1 release. These changes induced by HFpEF were exacerbated by MD1 deficiency. We conclude that MD1-KO contributes to sympathetic hyperactivity and facilitates VA in HFpEF via activation of the NLRP3 inflammasome. Treatment targeting MD1 and NLRP3 might decrease the risk of HFpEF-induced VA. K E Y W O R D Sheart failure with preserved ejection fraction, inflammation, sympathetic nerve 1 966wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:966-978.

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“…The combination of HFD and ANGII infusion induces hypertension, obesity and T2DM in young male mice. 151 , 190 , 191 This intervention also results in preserved LV function with diastolic dysfunction, concentric hypertrophy with fibrosis and increased natriuretic peptides. However, signs and symptoms or clinical features of HFpEF, if any, appear to be very mild since lung congestion in young animals is absent and effect on exercise capacity is unknown.…”

Section: Progress In Pre-clinical Hf Models: Development Of Multifactorial Modelsmentioning

confidence: 99%

Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models

Withaar

Lam

Schiattarella

et al. 2021

European Heart Journal

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Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans.

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Cilostazol ameliorates heart failure with preserved ejection fraction and diastolic dysfunction in obese and non-obese hypertensive mice

Cited by 29 publications

References 79 publications

Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation

Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models

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