Epoxylipids and soluble epoxide hydrolase in heart diseases.

Cardiovascular and heart diseases are leading causes of morbidity and mortality. Coronary artery endothelial and vascular dysfunction, inflammation, and mitochondrial dysfunction contribute to progression of heart diseases such as arrhythmias, congestive heart failure, and heart attacks. Classes of fatty acid epoxylipids and their enzymatic regulation by soluble epoxide hydrolase (sEH) have been implicated in coronary artery dysfunction, inflammation, and mitochondrial dysfunction in heart diseases. Likewise, genetic and pharmacological manipulations of epoxylipids have been demonstrated to have therapeutic benefits for heart diseases. Increasing epoxylipids reduce cardiac hypertrophy and fibrosis and improve cardiac function. Beneficial actions for epoxylipids have been demonstrated in cardiac ischemia reperfusion injury, electrical conductance abnormalities and arrhythmias, and ventricular tachycardia. This review discusses past and recent findings on the contribution of epoxylipids in heart diseases and the potential for their manipulation to treat heart attacks, arrhythmias, ventricular tachycardia, and heart failure.

The complex network of mTOR signalling in the heart.

The mechanistic target of rapamycin (mTOR) integrates several intracellular and extracellular signals involved in the regulation of anabolic and catabolic processes. mTOR assembles into two macromolecular complexes, named mTORC1 and mTORC2, which have different regulators, substrates and functions. Studies of gain- and loss-of-function animal models of mTOR signalling revealed that mTORC1/2 elicits both adaptive and maladaptive functions in the cardiovascular system. Both mTORC1 and mTORC2 are indispensable for driving cardiac development and cardiac adaption to stress, such as pressure overload. However, persistent and deregulated mTORC1 activation in the heart is detrimental during stress and contributes to the development and progression of cardiac remodelling and genetic and metabolic cardiomyopathies. In this review, we discuss the latest findings regarding the role of mTOR in the cardiovascular system, both under basal conditions and during stress, such as pressure overload, ischemia, and metabolic stress. Current data suggest that mTOR modulation may represent a potential therapeutic strategy for the treatment of cardiac diseases.

Physiological and pathological roles of protein kinase A in the heart.

Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters, and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind ß-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signalling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischaemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases.

The modulation of SIRT1 and SIRT3 by natural compounds as a therapeutic target in doxorubicin-induced cardiotoxicity: A review.

Doxorubicin (DOX) is a potent antitumor agent with a broad spectrum of activity; however, irreversible cardiotoxicity resulting from DOX treatment is a major issue that limits its therapeutic use. Sirtuins (SIRTs) play an essential role in several physiological and pathological processes including oxidative stress, apoptosis, and inflammation. It has been reported that SIRT1 and SIRT3 can act as a protective molecular against DOX-induced myocardial injury through targeting numerous signaling pathways. Several natural compounds (NCs), such as resveratrol, sesamin, and berberine, with antioxidative, anti-inflammation, and antiapoptotic effects were evaluated for their potential to suppress the cardiotoxicity induced by DOX via targeting SIRT1 and SIRT3. Numerous NCs exerted their therapeutic effects on DOX-mediated cardiac damage via targeting different signaling pathways, including SIRT1/LKB1/AMPK, SIRT1/PGC-1α, SIRT1/NLRP3, and SIRT3/FoxO. SIRT3 also ameliorates cardiotoxicity by enhancing mitochondrial fusion.

Curcumin Ameliorates Doxorubicin-Induced Cardiotoxicity and Hepatotoxicity Via Suppressing Oxidative Stress and Modulating iNOS, NF-κB, and TNF-α in Rats.

Doxorubicin (DOX) is one of the widely used anti-tumor drugs. However, DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) are among the side effects that limited its therapeutic efficiency and clinical applicability. This study aimed to investigate the cardioprotective and hepatoprotective potentials of curcumin (CMN)-a bioactive polyphenolic compound-in alleviating DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) in male rats. A single intraperitoneal (i.p.) dose of DOX (20 mg/kg) was used to induce DIC and DIH. DOX-intoxicated rats were co-treated with CMN (100 mg/kg, oral) for 10 days before and 5 days after a single dose of DOX. We studied the anti-inflammatory and anti-oxidative activities of CMN on biochemical and immunohistochemical aspects. DOX disrupted cardiac and hepatic functions and stimulated oxidative stress and inflammation in both tissues that was confirmed biochemically and immunohistochemically. DOX enhanced inflammatory interferon-gamma (IFN-γ) and upregulated immunoexpression of nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF-α). DOX induced structural alterations in both cardiac and hepatic tissues. CMN demonstrated cardioprotective potential through reducing cardiac troponin I (cTn1) and aspartate amino transaminase (AST). In addition, CMN significantly ameliorated liver function through decreasing alanine amino transaminase (ALT) and, gamma-glutamyl transferase (GGT), total cholesterol (TC), and triglycerides (TG). CMN demonstrated anti-inflammatory potential through decreasing IFN-γ levels and immunoexpression of iNOS, NF-κB, and TNF-α. Histopathologically, CMN restored DOX-associated cardiac and liver structural alterations. CMN showed anti-oxidative and anti-inflammatory potentials in both the cardiac and hepatic tissues. In addition, cTn1, IFN-γ, and AST could be used as blood-based biomarkers.

DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases.

Mitogen-activated protein kinases (MAPKs) are essential for proper cell functioning as they regulate many molecular effectors. Careful regulation of MAPKs is therefore required to avoid MAPK pathway dysfunctions and pathologies. The mammalian genome encodes about 200 phosphatases, many of which dephosphorylate the MAPKs and bring them back to an inactive state. In this review, we focus on the normal and pathological functions of dual-specificity phosphatase 9 (DUSP9)/MAP kinase phosphatases-4 (MKP-4). This cytoplasmic phosphatase, which belongs to the threonine/tyrosine dual-specific phosphatase family and was first described in 1997, is known to dephosphorylate ERK1/2, p38, JNK and ASK1, and thereby to control various MAPK pathway cascades. As a consequence, DUSP9 plays a major role in human pathologies and more specifically in cardiac dysfunction, liver metabolic syndromes, diabetes, obesity and cancer including drug response and cell stemness. Here, we recapitulate the mechanism of action of DUSP9 in the cell, its levels of regulation and its roles in the most frequent human diseases, and discuss its potential as a therapeutic target.

Apelin-13 Reverses Bupivacaine-Induced Cardiotoxicity via the Adenosine Monophosphate-Activated Protein Kinase Pathway.

BACKGROUND: Cardiotoxicity can be induced by the commonly used amide local anesthetic, bupivacaine. Bupivacaine can inhibit protein kinase B (AKT) phosphorylation and activated adenosine monophosphate-activated protein kinase alpha (AMPKα). It can decouple mitochondrial oxidative phosphorylation and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity. METHODS: We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined. RESULTS: Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002. CONCLUSIONS: Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity.

Dose-Dependent Cardioprotective Effect of Hemin in Doxorubicin-Induced Cardiotoxicity Via Nrf-2/HO-1 and TLR-5/NF-κB/TNF-α Signaling Pathways.

Doxorubicin (DOX) is one of the most widely used chemotherapeutic drugs, but its cardiotoxicity has been shown to be a dose-restricting factor during therapy. Finding new agents for reducing these complications is still in critical need. The current study aimed to evaluate the possible cardioprotective effect of hemin (HEM) in DOX-induced cardiotoxicity and exploring the role of toll like receptor-5/nuclear factor kappa-B/tumor necrosis factor-alpha (TLR-5/NF-κB/TNF-α) and nuclear factor erythroid 2-related factor-2/hemeoxygenase-1 (Nrf-2/HO-1) signaling pathways in mediating such effect. Wistar albino rats were randomly divided into five groups. They were administered DOX by interaperitoneal (i.p.) injection (15 mg/kg) on the 5th day of the experiment with or without HEM in different doses (2.5, 5, 10 mg/kg/day) i.p. for 7 days. Results showed that the DOX group had cardiotoxicity as manifested by a significant increase in cardiac enzymes, malondialdehyde (MDA), TLR-5, NF-κB, TNF-α, and cleaved caspase-3 levels with toxic histopathological changes. Based on these findings, HEM succeeded in reducing DOX-induced cardiotoxicity in a dose-dependent effect by stimulation of Nrf-2/HO-1 and inhibition of TLR-5/NF-κB/TNF-α pathways with subsequent antioxidant, anti-inflammatory, and anti-apoptotic effects.

Protopanaxadiol and Protopanaxatriol Ginsenosides Can Protect Against Aconitine-induced Injury in H9c2 Cells by Maintaining Calcium Homeostasis and Activating the AKT Pathway.

ABSTRACT: This study aimed to investigate the effects of protopanaxadiol and protopanaxatriol ginsenosides on aconitine-induced cardiomyocyte injury and their regulatory mechanisms. The effects of ginsenosides on aconitine-induced cardiomyocyte damage were initially evaluated using H9c2 cells, and the molecular mechanisms were elucidated using molecular docking and western blotting. The changes in enzyme content, reactive oxygen species (ROS), calcium (Ca2+) concentration, and apoptosis were determined. Furthermore, an aconitine-induced cardiac injury rat model was established, the cardiac injury and serum physiological and biochemical indexes were measured, and the effects of ginsenoside were observed. The results showed that ginsenoside Rb1 significantly increased aconitine-induced cell viability, and its binding conformation with protein kinase B (AKT) protein was the most significant. In vitro and in vivo, Rb1 protects cardiomyocytes from aconitine-induced injury by regulating oxidative stress levels and maintaining Ca2+ concentration homeostasis. Moreover, Rb1 activated the PI3K/AKT pathway, downregulated Cleaved caspase-3 and Bax, and upregulated Bcl-2 expression. In conclusion, Rb1 protected H9c2 cells from aconitine-induced injury by maintaining Ca2+ homeostasis and activating the PI3K/AKT pathway to induce a cascade response of downstream proteins, thereby protecting cardiomyocytes from damage. These results suggested that ginsenoside Rb1 may be a potential cardiac protective drug.

The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment.

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases.

The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease.

Despite advances in medicine, cardiac disease remains an increasing health problem associated with a high mortality rate. Maladaptive cardiac remodeling, such as cardiac hypertrophy and fibrosis, is a risk factor for heart failure; therefore, it is critical to identify new therapeutic targets. Failing heart is reported to be associated with hyper-ubiquitylation and impairment of the ubiquitin-proteasome system, indicating an importance of ubiquitylation in the development of cardiac disease. Ubiquitylation is a post-translational modification that plays a pivotal role in protein function and degradation. In 1995, homologous to E6AP C-terminus (HECT) type E3 ligases were discovered. E3 ligases are key enzymes in ubiquitylation and are classified into three families: really interesting new genes (RING), HECT, and RING-between-RINGs (RBRs). Moreover, 28 HECT-type E3 ligases have been identified in human beings. It is well conserved in evolution and is characterized by the direct attachment of ubiquitin to substrates. HECT-type E3 ligase is reported to be involved in a wide range of human diseases and health. The role of HECT-type E3 ligases in the development of cardiac diseases has been uncovered in the last decade. There are only a few review articles summarizing recent advancements regarding HECT-type E3 ligase in the field of cardiac disease. This study focused on cardiac remodeling and described the role of HECT-type E3 ligases in the development of cardiac disease. Moreover, this study revealed that the current knowledge could be exploited for the development of new clinical therapies.

Angiotensin (1-7) Alleviates Postresuscitation Myocardial Dysfunction by Suppressing Oxidative Stress Through the Phosphoinositide 3-Kinase, Protein Kinase B, and Endothelial Nitric Oxide Synthase Signaling Pathway.

ABSTRACT: There is increasing evidence that angiotensin (1-7) [Ang (1-7)] is an endogenous biologically active component of the renin-angiotensin system. However, the role of the Ang (1-7)-MasR axis in postresuscitation myocardial dysfunction (PRMD) and its associated mechanism are still unclear. In this study, we investigated the effect of the Ang (1-7)-MasR axis on myocardial injury after cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation. We established a model of oxygen/glucose deprivation-reperfusion in myocardial cells in vitro and a rat model of cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation in vivo. The cell apoptosis rate and the expression of the superoxide anion 3-nitrotyrosine were decreased in the Ang (1-7) group in vitro and in vivo. The mean arterial pressure was decreased, whereas +LVdp/dtmax and -LVdp/dtmax were increased in rats in the Ang (1-7) group. The mRNA and protein levels of Ang II type 1 receptor, MasR, phosphoinositide 3-kinase, protein kinase B, and endothelial nitric oxide synthase were increased in the Ang (1-7) group in vivo. These results indicate that the Ang (1-7)-MasR axis can alleviate PRMD by reducing myocardial tissue damage and oxidative stress through activation of the phosphoinositide 3-kinase-protein kinase B-endothelial nitric oxide synthase signaling pathway and provide a new direction for the clinical treatment of PRMD.

Chrysin Ameliorates Sepsis-Induced Cardiac Dysfunction Through Upregulating Nfr2/Heme Oxygenase 1 Pathway.

ABSTRACT: The incidence of myocardial dysfunction caused by sepsis is high, and the mortality of patients with sepsis can be significantly increased. During sepsis, oxidative stress and inflammation can lead to severe organ dysfunction. Flavone chrysin is one of the indispensable biological active ingredients for different fruits and vegetables and has antioxidant and anti-inflammatory properties. However, it is not clear whether chrysin is an effective treatment for heart dysfunction caused by sepsis. We found that it had protective effects against the harmful effects caused by LPS, manifested in improved survival, normalized cardiac function, improved partial pathological scores of myocardial tissue, and remission of apoptosis, as well as reduced oxidative stress and inflammation. Mechanism studies have found that chrysin is an important antioxidant protein, a key regulator of heme oxygenase 1 (HO-1). We found that HO-1 levels were increased after LPS intervention, and chrysin further increased HO-1 levels, along with the addition of Nrf2, a regulator of antioxidant proteins. Pretreatment with PD98059, an extracellular signal-regulated kinase-specific inhibitor, blocked chrysin-mediated phosphorylation of Nrf2 and the nuclear translocation of Nrf2. The protective effect of chrysin on sepsis-induced cardiac dysfunction was blocked by ZnPP, which is a HO-1 blocker. Chrysin increased antioxidant activity and reduced markers of oxidative stress (SOD and MDA) and inflammation (MPO and IL-1ß), all of which were blocked by ZnPP. This indicates that HO-1 is the upstream molecule regulating the protective effect of chrysin. Thus, by upregulation of HO-1, chrysin protects against LPS-induced cardiac dysfunction and inflammation by inhibiting oxidative stress.

Moderate offspring exercise offsets the harmful effects of maternal protein deprivation on mitochondrial function and oxidative balance by modulating sirtuins.

BACKGROUND AND AIMS: It has been demonstrated that maternal low protein during development induces mitochondrial dysfunction and oxidative stress in the heart. Moderate-intensity exercise in early life, conversely, increases the overall cardiac health. Thus, we hypothesize that moderate-intensity exercise performed during young age could ameliorate the deleterious effect of maternal protein deprivation on cardiac bioenergetics. METHODS AND RESULTS: We used a rat model of maternal protein restriction during gestational and lactation period followed by an offspring treadmill moderate physical training. Pregnant rats were divided into two groups: normal nutrition receiving 17% of casein in the diet and undernutrition receiving a low-protein diet (8% casein). At 30 days of age, the male offspring were further subdivided into sedentary (NS and LS) or exercised (NT and LT) groups. Treadmill exercise was performed as follows: 4 weeks, 5 days/week, 60 min/day at 50% of maximal running capacity. Our results showed that a low-protein diet decreases oxidative metabolism and mitochondrial function associated with higher oxidative stress. In contrast, exercise rescues mitochondrial capacity and promotes a cellular resilience to oxidative stress. Up-regulation of cardiac sirtuin 1 and 3 decreased acetylation levels, redeeming from the deleterious effect of protein restriction. CONCLUSION: Our findings show that moderate daily exercise during a young age acts as a therapeutical intervention opposing the harmful effects of a maternal diet restricted in protein.

Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression.

AIMS: Patients with severe respiratory syndrome caused by SARS-CoV-2 undergo cardiac complications due to hyper-inflammatory conditions. Although the presence of the virus has been detected in the myocardium of infected patients, and infection of induced pluripotent cell-derived cardiomyocytes has been demonstrated, the reported expression of Angiotensin-Converting Enzyme-2 (ACE2) in cardiac stromal cells suggests that SARS-CoV-2 may determine cardiac injury by sustaining productive infection and increasing inflammation. METHODS AND RESULTS: We analysed expression of ACE2 receptor in primary human cardiac stromal cells derived from cardiospheres, using proteomics and transcriptomics before exposing them to SARS-CoV-2 in vitro. Using conventional and high sensitivity PCR methods, we measured virus release in the cellular supernatants and monitored the intracellular viral bioprocessing. We performed high-resolution imaging to show the sites of intracellular viral production and demonstrated the presence of viral particles in the cells with electron microscopy. We finally used RT-qPCR assays to detect genes linked to innate immunity and fibrotic pathways coherently regulated in cells after exposure to the virus. CONCLUSIONS: Our findings indicate that cardiac stromal cells are susceptible to SARS-CoV-2 infection and produce variable viral yields depending on the extent of cellular ACE2 receptor expression. Interestingly, these cells also evolved towards hyper-inflammatory/pro-fibrotic phenotypes independently of ACE2 levels. Thus, SARS-CoV-2 infection of myocardial stromal cells could be involved in cardiac injury and explain the high number of complications observed in severe cases of COVID-19.

MiR-200a-3p Aggravates DOX-Induced Cardiotoxicity by Targeting PEG3 Through SIRT1/NF-κB Signal Pathway.

Doxorubicin (DOX) is a widely used cytotoxic drug whose application is limited by its severe side effects. Little was known regarding how to offset its side effects. Therefore this study aims to explore the role of miR-200a-3p in DOX-induced cardiotoxicity and its possible mechanism. DOX-induced myocardial injury rat models were established, which were then injected with miR-200a-3p inhibitor (miR-200a-3p suppression) to observe the effects of miR-200a-3p on cell proliferation, and apoptosis. Heart function and weights of rat models were also measured. Cardiomyocytes were induced by DOX, in which PEG3 knockdown or corresponding plasmids were transfected to assess the possible effect of PEG3 on cell activity. Dual luciferase reporter assay was applied to verify the binding of PEG3 with miR-200a-3p. Elevated levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and left ventricular end-diastolic pressure (LVEDP), as well as suppressed left ventricular systolic pressure (LVSP) and ± dp/dt max were showed in myocardial injury rat models. DOX induced myocardial injury and increased miR-200a-3p expression levels. miR-200a-3p inhibitor could partially attenuate DOX-induced cardiotoxicity in rat models, while PEG3 could regulate myocardial injury in DOX-treated cell models. miR-200a-3p, by targeting PEG3 through SIRT1/NF-κB signal pathway, regulated cell proliferation, inflammation and apoptosis of myocardiocytes. The results in current study demonstrated that miR-200a-3p regulates cell proliferation and apoptosis of cardiomyocytes by targeting PEG3 through SIRT1/NF-κB signal pathway. This result may provide a potential clue for the treatment of DOX-induced cardiotoxicity.

Melatonin Alleviates Cardiac Dysfunction Via Increasing Sirt1-Mediated Beclin-1 Deacetylation and Autophagy During Sepsis.

Cardiac dysfunction is a major cause leading to multiple organ failure in sepsis. Beclin-1-dependent autophagy has been evidenced to exert protective effects on hearts in sepsis. However, the mechanisms on how Beclin-1 and autophagy are regulated remains enigmatic. To explore the detailed mechanisms controlling Beclin-1-dependent autophagy in septic heart and whether melatonin could protect against sepsis via regulating cardiac autophagy, adult Sprague-Dawley (SD) rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Rats were intraperitoneally administrated with 30 mg/kg melatonin within 5-min post-CLP surgery. Our data showed that sepsis induced Becline-1 acetylation and inhibited autophagy in hearts, resulting in impaired cardiac function. However, melatonin treatment facilitated Beclin-1 deacetylation and increased autophagy in septic hearts, thus improved cardiac function. Moreover, melatonin increased the expression and activity of Sirtuin 1 (Sirt1), and inhibition of Sirt1 abolished the protective effects of melatonin on Beclin-1 deacetylation and cardiac function. In conclusion, increased Beclin-1 acetylation was involved in impaired autophagy in septic hearts, while melatonin contributed to Beclin-1 deacetylation via Sirt1, leading to improved autophagy and cardiac function in sepsis. Our study sheds light on the important role of Beclin-1 acetylation in regulating autophagy in sepsis and suggests that melatonin is a potential candidate drug for the treatment of sepsis.

Mitochondrial Sirtuins and Doxorubicin-induced Cardiotoxicity.

Doxorubicin (DOX) is the most effective and extensively used treatment for many tumors. However, its clinical use is hampered by its cardiotoxicity. DOX-induced mitochondrial dysfunction, which causes reactive oxygen species (ROS) generation, cardiomyocyte death, bioenergetic failure, and decreased cardiac function, is a very important mechanism of cardiotoxicity. These cellular processes are all linked by mitochondrial sirtuins (SIRT3-SIRT4). Mitochondrial sirtuins preserve mitochondrial function by increasing mitochondrial metabolism, inhibiting ROS generation by activating the antioxidant enzyme manganese-dependent superoxide dismutase (MnSOD), decreasing apoptosis by activating the forkhead homeobox type O (FOXO) and P53 pathways, and increasing autophagy through AMP-activated protein kinase (AMPK)/mTOR signaling. Thus, sirtuins function at the control point of many mechanisms involved in DOX-induced cardiotoxicity. In this review, we focus on the role of mitochondrial sirtuins in mitochondrial biology and DOX-induced cardiotoxicity. A further aim is to highlight other mitochondrial processes, such as autophagy (mitophagy) and mitochondrial quality control (MQC), for which the effect of mitochondrial sirtuins on cardiotoxicity is unknown.

Angiotensin-converting enzyme 2 and COVID-19 in cardiorenal diseases.

The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications.

Inhibition of ATGL in adipose tissue ameliorates isoproterenol-induced cardiac remodeling by reducing adipose tissue inflammation.

Following cardiac injury, increased adrenergic drive plays an important role in compensating for reduced cardiac function. However, chronic excess adrenergic stimulation can be detrimental to cardiac pathophysiology and can also affect other organs including adipose tissue, leading to increased lipolysis. Interestingly, inhibition of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in lipolysis, in adipocytes ameliorates cardiac dysfunction in a heart failure model. Thus, we investigated whether inhibition of adipocyte ATGL can mitigate the adverse cardiac effects of chronic adrenergic stimulation and explored the underlying mechanisms. To do this, isoproterenol (ISO) was continuously administered to C57Bl/6N mice for 2 wk with or without an ATGL inhibitor (Atglistatin). We found that Atglistatin alleviated ISO-induced cardiac remodeling and reduced ISO-induced upregulation of galectin-3, a marker of activated macrophages and a potent inducer of fibrosis, in white adipose tissue (WAT), heart, and the circulation. To test whether the beneficial effects of Atglistatin occur via inhibition of adipocyte ATGL, adipocyte-specific ATGL knockout (atATGL-KO) mice were utilized for similar experiments. Subsequently, the same cardioprotective effects of atATGL-KO following ISO administration were observed. Furthermore, Atglistatin and atATGL-KO abolished ISO-induced galectin-3 secretion from excised WAT. We further demonstrated that activation of cardiac fibroblasts by the conditioned media of ISO-stimulated WAT is galectin-3-dependent. In conclusion, the inhibition of adipocyte ATGL ameliorated ISO-induced cardiac remodeling possibly by reducing galectin-3 secretion from adipose tissue. Thus, inhibition of adipocyte ATGL might be a potential target to prevent some of the adverse effects of chronic excess adrenergic drive.NEW & NOTEWORTHY The reduction of lipolysis by adipocyte ATGL inhibition ameliorates cardiac remodeling induced by chronic ß-adrenergic stimulation likely via reducing galectin-3 secretion from adipose tissue. Our findings highlight that suppressing lipolysis in adipocytes may be a potential therapeutic target for patients with heart failure whose sympathetic nervous system is activated. Furthermore, galectin-3 might be involved in the mechanisms by which excessive lipolysis in adipose tissues influences remote cardiac pathologies and thus warrants further investigation.