Mountainous evidence suggests that inflammation, cardiomyocyte apoptosis and pyroptosis are involved in the development of sepsis and sepsis-induced cardiomyopathy (SIC). Stimulator of interferon genes (STING) is an indispensable molecule that could regulate inflammation and immune response in multiple diseases. However, the role of STING in cardiovascular disease, especially SIC remains unclear. This study was designed to investigate the potential molecular mechanisms of STING in lipopolysaccharide (LPS)-induced cardiac injury using STING global knockout mice. In wild type mice and cardiomyocytes, LPS stimulation triggered the perinuclear translocation of STING, which further bound to Type-I interferons (IFN) regulatory factor 3 (IRF3) and phosphorylated IRF3. Phosphorylated (P-) IRF3 subsequently translocated into nucleus and increased the expression of NOD-like receptor protein 3 (NLRP3). Knockout of STING in mice significantly improved survival rate and cardiac function, apart from suppressing myocardial and serum inflammatory cytokines, apoptosis, as well as cardiomyocyte pyroptosis. In vitro experiments revealed that NLRP3 overexpression by adenovirus could offset protective effects of STING knockdown in LPS-induced cardiomyocytes. Additionally, LPS stimulation also promoted the production of intracellular reactive oxygen (ROS), which further induced the NLRP3 translocation to the cytoplasm from the nucleus. Dissociative TXNIP could directly interact with cytoplasmic NLRP3 and form inflammasome, eventually triggering cardiomyocyte injury. Collectively, our findings disclose that STING deficiency could alleviate LPS-induced SIC in mice. Hence, targeting STING in cardiomyocytes may be a promising therapeutic strategy for preventing SIC.

STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3

Numerous studies have demonstrated that endothelial cells are capable of undergoing endothelial to mesenchymal transition (EndMT), a newly recognized type of cellular transdifferentiation. EndMT is...

Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases.

Rutaecarpine: A promising cardiovascular protective alkaloid from Evodia rutaecarpa (Wu Zhu Yu).

The nod-like receptor family pyrin domain containing 3 (NLRP3) is currently the most widely studied inflammasome and has become a hot topic of recent research As a macromolecular complex, the NLRP3 inflammasome is activated to produce downstream factors, including caspase-1, IL-1β, and IL-18, which then promote local inflammatory responses and induce pyroptosis, leading to unfavorable effects A growing number of studies have examined the relationship between the NLRP3 inflammasome and cardiovascular diseases (CVDs) However, some studies have shown that the NLRP3 inflammasome is not involved in the occurrence of certain diseases Therefore, identifying the mechanism of action of the NLRP3 inflammasome and its potential involvement in the pathological process of disease progression is of utmost importance This review discusses the mechanisms of NLRP3 inflammasome activation and the relationship between the inflammasome and CVDs, including coronary atherosclerosis, myocardial ischemia/reperfusion, cardiomyopathies, and arrhythmia, as well as CVD-related treatments

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Regulatory Mechanisms of the NLRP3 Inflammasome, a Novel Immune-Inflammatory Marker in Cardiovascular Diseases

Heart is the most active and incumbent organ of the body, which maintains blood flow, but due to various pathological reasons, several acute and chronic cardiac complications arise out of which myocardial infarction is one of the teething problems. Isoproterenol (ISP)-induced myocardial ischemia is a classical model to screen the cardioprotective effects of various pharmacological interventions. Phytochemicals present a novel option for treating various human maladies including those of the heart. A large number of plant products and their active ingredients have been screened for efficacy in ameliorating ISP-induced myocardial ischemia including coriander, curcumin, Momordica, quercetin, and Withania somnifera. These phytochemicals constituents may play key role in preventing disease and help in cardiac remodeling. Reactive oxygen species scavenging, antiinflammatory, and modulation of various molecular pathways such as Nrf2, NFкB, p-21 activated kinase 1 (PAK1), and p-smad2/3 signaling modulation have been implicated behind the claimed protection. In this review, we have provided a focused overview on the utility of ISP-induced cardiotoxicity, myocardial ischemia, and cardiac fibrosis for preclinical research. In addition, we have also surveyed molecular mechanism of various plant-based interventions screened for cardioprotective effect in ISP-induced cardiotoxicity, and their probable mechanistic profile is summarized.

Isoproterenol-induced cardiac ischemia and fibrosis: Plant-based approaches for intervention

Lack of effective anti-cardiac hypertrophy drugs creates a major cause for the increasing prevalence of heart failure. In the present study, we determined the anti-hypertrophy and anti-fibrosis potential of a natural plant triterpenoid, Cucurbitacin B both in vitro and in vivo. Aortic banding (AB) was performed to induce cardiac hypertrophy. After 1 week of surgery, mice were receive cucurbitacin B treatment (Gavage, 0.2 mg/kg body weight/2 day). After 4 weeks of AB, cucurbitacin B demonstrated a strong anti-hypertrophy and -fibrosis ability as evidenced by decreased of heart weight, myocardial cell cross-sectional area and interstitial fibrosis, ameliorated of systolic and diastolic abnormalities, normalized in gene expression of hypertrophic and fibrotic markers, reserved microvascular density in pressure overload induced hypertrophic mice. Cucurbitacin B also showed significant hypertrophy inhibitory effect in phenylephrine stimulated cardiomyocytes. The Cucurbitacin B-mediated mitigated cardiac hypertrophy was attributable to the increasing level of autophagy, which was associated with the blockade of Akt/mTOR/FoxO3a signal pathway, validated by SC79, MK2206, and 3-MA, the Akt agonist, inhibitor and autophagy inhibitor in vitro. The overexpression of constitutively active Akt completely abolished the Cucurbitacin B-mediated protection of cardiac hypertrophy in human cardiomyocytes AC16. Collectively, our findings suggest that cucurbitacin B protects against cardiac hypertrophy through increasing the autophagy level in cardiomyocytes, which is associated with the inhibition of Akt/mTOR/FoxO3a signal axis. J. Cell. Biochem. 118: 3899-3910, 2017. © 2017 Wiley Periodicals, Inc.

Cucurbitacin B Protects Against Pressure Overload Induced Cardiac Hypertrophy

BACKGROUND AND PURPOSE Aucubin, the predominant component of Eucommia ulmoides Oliv., has been shown to have profound effects on oxidative stress. As oxidative stress has previously been demonstrated to contribute to acute and chronic myocardial injury, we tested the effects of aucubin on cardiac remodelling and heart failure. EXPERIMENTAL APPROACH Initially, H9c2 cardiomyocytes and neonatal rat cardiomyocytes pretreated with aucubin (1, 3, 10, 25 and 50 μM) were challenged with phenylephrine. Secondly, the transverse aorta was constricted in C57/B6 and neuronal NOS (nNOS)-knockout mice, then aucubin (1 or 5 mg·kg-1 body weight day-1 ) was injected i.p. for 25 days. Hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, histological analyses and hypertrophic markers. Oxidative stress was evaluated by examining ROS generation, oxidase activity and NO generation. NOS expression was determined by Western blotting. KEY RESULTS Aucubin effectively suppressed cardiac remodelling; in mice, aucubin substantially inhibited pressure overload-induced cardiac hypertrophy, fibrosis and inflammation, whereas knocking out nNOS abolished these cardioprotective effects of aucubin. Blocking or knocking down the β3 -adrenoceptor abolished the protective effects of aucubin in vitro. Furthermore, aucubin enhanced the protective effects of a β3 -adrenoceptor agonist in vitro by increasing cellular cAMP levels, whereas treatment with an adenylate cyclase (AC) inhibitor abolished the cardioprotective effects of aucubin. CONCLUSIONS AND IMPLICATIONS Aucubin suppresses oxidative stress during cardiac remodelling by increasing the expression of nNOS in a process that requires activation of the β3 -adrenoceptor/AC/cAMP pathway. These findings suggest that aucubin could have potential as a treatment for cardiac remodelling and heart failure.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.14164

Aucubin protects against pressure overload-induced cardiac remodelling via the β3 -adrenoceptor-neuronal NOS cascades.

The aim of this study is to investigate the effect of evodiamine on fibroblast activation in cardiac fibroblasts and endothelial to mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs). Neonatal rat cardiac fibroblasts were stimulated with transforming growth factor beta 1 (TGF-β1) to induce fibroblast activation. After co-cultured with evodiamine (5, 10 μM), the proliferation and pro-fibrotic proteins expression of cardiac fibroblasts were evaluated. HUVECs were also stimulated with TGF-β1 to induce EndMT and treated with evodiamine (5, 10 μM) at the same time. The EndMT response in the HUVECs was evaluated as well as the capacity of the transitioned endothelial cells migrating to surrounding tissue. As a result, Evodiamine-blunted TGF-β1 induced activation of cardiac fibroblast into myofibroblast as assessed by the decreased expressions of α-SMA. Furthermore, evodiamine reduced the increased protein expression of fibrosis markers in neonatal and adult rat cardiac fibroblasts induced by TGF-β1. HUVECs stimulated with TGF-β1 exhibited lower expression levels of CD31, CD34, and higher levels of α-SMA, vimentin than the control cells. This phenotype was eliminated in the HUVECs treated with both 5 and 10 μM evodiamine. Evodiamine significantly reduced the increase in migration ability that occurred in response to TGF-β1 in HUVECs. In addition, the activation of Smad2, Smad3, ERK1/2, and Akt, and the nuclear translocation of Smad4 in both cardiac fibroblasts and HUVEC were blocked by evodiamine treatment. Thus, evodiamine could prevent cardiac fibroblasts from activation into myofibroblast and protect HUVEC against EndMT. These effects may be mediated by inhibition of the TGFβ pathway in both cardiac fibroblasts and HUVECs.

Evodiamine attenuates TGF-β1-induced fibroblast activation and endothelial to mesenchymal transition.

Acacetin protects against cardiac remodeling after myocardial infarction by mediating MAPK and PI3K/Akt signal pathway.

Evodiamine, a major component of Evodia rutaecarpa, can protect the myocardium against injury induced by atherosclerosis and ischemia-reperfusion. However, the effect of evodiamine against cardiac fibrosis remains unclear. This study aims to investigate the possible effect and mechanism involved in the function of evodiamine on isoproterenol-induced cardiac fibrosis and endothelial-to-mesenchymal transition. Isoproterenol was used to induce cardiac fibrosis in mice, and evodiamine was gavaged simultaneously. After 14 days, cardiac function was accessed by echocardiography. The extent of cardiac fibrosis and hypertrophy was evaluated by pathological and molecular analyses. The extent of endothelial-to-mesenchymal transition was evaluated by the expression levels of CD31, CD34, α-smooth muscle actin, and vimentin by immunofluorescence staining and Western blot analysis. After 14 days, the heart weight/body weight ratio and heart weight/tibia length ratio revealed no significant difference between the isoproterenol group and the isoproterenol/evodiamine-treated groups, whereas the increased heart weight was reduced in the isoproterenol/evodiamine-treated groups. Echocardiography revealed that interventricular septal thickness and left ventricular posterior wall thickness at the end diastole decreased in the evodiamine-treated groups. Evodiamine reduced isoproterenol-induced cardiac fibrosis as accessed by normalization in collagen deposition and gene expression of hypertrophic and fibrotic markers. Evodiamine also prevented endothelial-to-mesenchymal transition as evidenced by the increased expression levels of CD31 and CD34, decreased expression levels of α-smooth muscle actin and vimentin, and increased microvascular density in the isoproterenol/evodiamine-treated mice hearts. Furthermore, isoproterenol-induced activation of transforming growth factor-β1/Smad signal was also blunted by evodiamine. Therefore, evodiamine may prevent isoproterenol-induced cardiac fibrosis by regulating endothelial-to-mesenchymal transition, which is probably mediated by the blockage of the transforming growth factor-β1/Smad pathway.

Xiao-Han Jiang

Papers

Cucurbitacin B Protects Against Pressure Overload Induced Cardiac Hypertrophy

Aucubin protects against pressure overload-induced cardiac remodelling via the β3 -adrenoceptor-neuronal NOS cascades.

Evodiamine attenuates TGF-β1-induced fibroblast activation and endothelial to mesenchymal transition.

Acacetin protects against cardiac remodeling after myocardial infarction by mediating MAPK and PI3K/Akt signal pathway.

Evodiamine Prevents Isoproterenol-Induced Cardiac Fibrosis by Regulating Endothelial-to-Mesenchymal Transition.