Metallothionein Alleviates Glutathione Depletion-Induced Oxidative Cardiomyopathy through CISD1-Dependent Regulation of Ferroptosis in Murine Hearts.

This study was designed to discern the effect of heavy scavenger metallothionein on glutathione (GSH) deprivation-evoked cardiac anomalies and mechanisms involved with an emphasis on ferroptosis. Wild-type and cardiac metallothionein transgenic mice received GSH synthase inhibitor buthionine sulfoximine (BSO; 30 mmol/L in drinking water) for 14 days before assessment of myocardial morphology and function. BSO evoked cardiac remodeling and contractile anomalies, including cardiac hypertrophy, interstitial fibrosis, enlarged left ventricular chambers, deranged ejection fraction, fraction shortening, cardiomyocyte contractile capacity, intracellular Ca2+ handling, sarcoplasmic reticulum Ca2+ reuptake, loss of mitochondrial integrity (mitochondrial swelling, loss of aconitase activity), mitochondrial energy deficit, carbonyl damage, lipid peroxidation, ferroptosis, and apoptosis. Metallothionein itself did not affect myocardial morphology and function, although it mitigated BSO-provoked myocardial anomalies, loss of mitochondrial integrity and energy, and ferroptosis. Immunoblotting revealed down-regulated sarco(endo)plasmic reticulum Ca2+-ATPase 2a, glutathione peroxidase 4, ferroptosis-suppressing CDGSH iron-sulfur domain 1 (CISD1), and mitochondrial regulating glycogen synthase kinase-3ß phosphorylation with elevated p53, myosin heavy chain-ß isozyme, IκB phosphorylation, and solute carrier family 7 member 11 (SLC7A11) as well as unchanged SLC39A1, SLC1A5, and ferroptosis-suppressing protein 1 following BSO challenge, all of which, except glutamine transporter SLC7A11 and p53, were abrogated by metallothionein. Inhibition of CISD1 using pioglitazone nullified GSH-offered benefit against BSO-induced cardiomyocyte ferroptosis and contractile and intracellular Ca2+ derangement. Taken together, these findings support a regulatory modality for CISD1 in the impedance of ferroptosis in metallothionein-offered protection against GSH depletion-evoked cardiac aberration.

Targeting ferroptosis in the maintenance of mitochondrial homeostasis in the realm of septic cardiomyopathy.

Septic cardiomyopathy is one of the predominant culprit factors contributing to the rising mortality in patients with severe sepsis. Among various mechanisms responsible for the etiology of septic heart anomalies, disruption of mitochondrial homeostasis has gained much recent attention, resulting in myocardial inflammation and even cell death. Ferroptosis is a novel category of regulated cell death (RCD) provoked by iron-dependent phospholipid peroxidation through iron-mediated phospholipid (PL) peroxidation, enroute to the rupture of plasma membranes and eventually cell death. This review summarizes the recent progress of ferroptosis in mitochondrial homeostasis during septic cardiomyopathy. We will emphasize the role of mitochondrial iron transport channels and the antioxidant system in ferroptosis. Finally, we will summarize and discuss future research, which should help guide disease treatment.

Beneficial impact of cardiac heavy metal scavenger metallothionein in sepsis-provoked cardiac anomalies dependent upon regulation of endoplasmic reticulum stress and ferroptosis but not autophagy.

AIMS: Sepsis represents a profound proinflammatory response with a major contribution from oxidative injury. Here we evaluated possible impact of heavy metal scavenger metallothionein (MT) on endotoxin lipopolysaccharide (LPS)-induced oxidative stress, endoplasmic reticulum (ER) stress, autophagy, and ferroptosis enroute to myocardial injury along with interplay among these stress domains. MATERIALS AND METHODS: Echocardiographic, cardiomyocyte mechanical and intracellular Ca2+ responses were monitored in myocardia from WT and transgenic mice with cardiac-selective MT overexpression challenged with LPS. Oxidative stress, stress signaling (p38, ERK, JNK), ER stress, autophagy, and ferroptosis were scrutinized. KEY FINDINGS: RNAseq analysis revealed discrepant patterns in ferroptosis between LPS-exposed and normal murine hearts. LPS insult enlarged LV end systolic dimension, suppressed fractional shortening, ejection fraction, maximal velocity of shortening/relengthening and peak shortening, as well as elongated relengthening along with dampened intracellular Ca2+ release and reuptake. In addition, LPS triggered oxidative stress (lowered glutathione/glutathione disulfide ratio and O2- production), activation of stress cascades (p38, ERK, JNK), ER stress (GRP78, PERK, Gadd153, and IRE1α), inflammation (TNFα and iNOS), unchecked autophagy (LCB3, Beclin-1 and Atg7), ferroptosis (GPx4 and SLC7A11) and interstitial fibrosis. Although MT overexpression itself did not reveal response on cardiac function, it attenuated or mitigated LPS-evoked alterations in echocardiographic, cardiomyocyte contractile and intracellular Ca2+ characteristics, O2- production, TNFα level, ER stress and ferroptosis (without affecting autophagy, elevated AMP/ATP ratio, and iNOS). In vitro evidence revealed beneficial effects of suppression of oxidative stress, ER stress and ferroptosis against LPS-elicited myocardial anomalies. SIGNIFICANCE: These data strongly support the therapeutic promises of MT and ferroptosis in septic cardiomyopathy.

Cardiomyocyte-specific deletion of endothelin receptor A (ETA) obliterates cardiac aging through regulation of mitophagy and ferroptosis.

Advanced aging evokes unfavorable changes in the heart including cardiac remodeling and contractile dysfunction although the underlying mechanism remains elusive. This study was conducted to evaluate the role of endothelin-1 (ET-1) in the pathogenesis of cardiac aging and mechanism involved. Echocardiographic and cardiomyocyte mechanical properties were determined in young (5-6 mo) and aged (26-28 mo) wild-type (WT) and cardiomyocyte-specific ETA receptor knockout (ETAKO) mice. GSEA enrichment identified differentially expressed genes associated with mitochondrial respiration, mitochondrial protein processing and mitochondrial depolarization in cardiac aging. Aging elevated plasma levels of ET-1, Ang II and suppressed serum Fe2+, evoked cardiac remodeling (hypertrophy and interstitial fibrosis), contractile defects (fractional shortening, ejection fraction, cardiomyocyte peak shortening, maximal velocity of shortening/relengthening and prolonged relengthening) and intracellular Ca2+ mishandling (dampened intracellular Ca2+ release and prolonged decay), the effects with the exception of plasma AngII, ET-1 and Fe2+ were mitigated by ETAKO. Advanced age facilitated O2- production, carbonyl protein damage, cardiac hypertrophy (GATA4, ANP, NFATc3), ER stress, ferroptosis, compromised autophagy (LC3B, Beclin-1, Atg7, Atg5 and p62) and mitophagy (parkin and FUNDC1), and deranged intracellular Ca2+ proteins (SERCA2a and phospholamban), the effects of which were reversed by ETA ablation. ET-1 provoked ferroptosis in vitro, the response was nullified by the ETA receptor antagonist BQ123 and mitophagy inducer CsA. ETA but not ETB receptor antagonism reconciled cardiac aging, which was abrogated by inhibition of mitophagy and ferroptosis. These findings collectively denote promises of targeting ETA, mitophagy and ferroptosis in the management of aging-associated cardiac remodeling and contractile defect.

Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced cardiac anomalies through reconciliation of autophagy and ferroptosis.

Lipopolysaccharide (LPS) from Gram-negative bacteria is a major contributor to cardiovascular failure, but the signaling mechanisms underlying its stress response are not fully understood. This study aimed to investigate the effect of the antioxidant enzyme catalase on LPS-induced cardiac abnormalities and the mechanisms involved, with particular focus on the interplay between autophagy, ferroptosis, and apoptosis. Cardiac-specific catalase (CAT) overexpression and wild-type (WT) mice were stimulated with LPS (6 mg/kg, intravenous injection), and cardiac morphology and function were evaluated. Oxidative stress, ferroptosis, apoptosis, and mitochondrial status were monitored, and survival curves were plotted based on the results of LPS stimulation. The results showed that, compared with WT mice, mice overexpressing catalase had a higher survival rate under LPS stimulation. Ultrasound echocardiography, cardiomyocyte characteristics, and Masson's trichrome staining showed that LPS inhibited cardiac function and caused cardiac fibrosis, while catalase alleviated these adverse effects. LPS increased apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), increased O2·- production, induced inflammation (TNF-α), autophagy, iron toxicity, and carbonyl damage, and significantly damaged mitochondria (mitochondrial membrane potential, mitochondrial proteins, and ultrastructure). These effects were significantly alleviated by catalase. Interestingly, the antioxidant N-acetylcysteine, autophagy inhibitor 3-methyladenine, and ferroptosis inhibitor lipostatin-1 all eliminated the LPS-induced contraction dysfunction and ferroptosis (using lipid peroxidation). Induction of ferroptosis could eliminate the cardioprotective effect of NAC. In conclusion, catalase rescues LPS-induced cardiac dysfunction by regulating oxidative stress, autophagy, ferroptosis, apoptosis, and mitochondrial damage in cardiomyocytes.

A Predictive Model for 30-Day Mortality of Fungemia in ICUs.

Background: Few predictive models have been established to predict the risk of 30-day mortality from fungemia. This study aims to create a nomogram to predict the 30-day mortality of fungemia in ICUs. Methods: Data of ICU patients with fungemia from both the Medical Information Mart for Intensive Care (MIMIC-III) database and the Grade-III Class-A hospital in China were collected. The data extracted from the MIMIC-III database functioned as the training dataset, which was used to construct a predictive model for 30-day mortality risk in ICU patients with fungemia; the data from the hospital functioned as the validation dataset, which was used to validate the model. A predictive model for 30-day mortality risk in ICU patients with fungemia was then built based on R software. Such indicators as C-index and calibration curve were utilized to evaluate the prediction ability of the model. Data of ICU patients with fungemia from the hospital were used as a validation dataset to validate the model. Results: Predictive models were constructed by age, international normalized ratio (INR), renal failure, liver disease, respiratory rate (RR), glucocorticoid therapy, antifungal therapy, and platelets. The C-index value of the models was 0.838 (95% CI: 0.79096-0.88504). Attested by external validation results, the model has satisfactory predictive ability. Conclusion: The 30-day mortality risk predictive model for ICU patients with fungemia constructed in this study has good predictive ability and may hopefully provide a 30-day mortality risk screening tool for ICU patients with fungemia.

Irisin Protects Against LPS-Stressed Cardiac Damage Through Inhibiting Inflammation, Apoptosis, and Pyroptosis.

ABSTRACT: Septic cardiac dysfunction remains a clinical problem due to its high morbidity and mortality. Uncontrolled cell death and excessive inflammatory response are closely related to sepsis-induced cardiac dysfunction. Irisin has been found to play cardioprotective roles in sepsis. However, there is enough uncertainty in the mechanism of irisin-mediated cardioprotection. We hypothesized that irisin may ameliorate myocardial dysfunction via reducing cardiac apoptosis, pyroptosis, and inflammation during LPS-induced sepsis. Mice were subjected to LPS with or without irisin treatment. After stimuli of LPS, the function of myocardium was distinctly impaired, which was closely related to increased level of apoptosis (decreased expression of Bcl-2 and elevated expression of Caspase-3 and Bax), pyroptosis (increased expression of Caspase1, NLR family pyrin domain containing 3 (NLRP3), and gasdermin D) and inflammatory mediators (increased level of IL-1ß, TNF-α, and IL-6). This process is consistent with increased toll-like receptor 4 (TLR4)/nuclear factor-kappa B signal, apoptotic signal, and NLRP3-mediated pyroptotic signal. Activation of apoptosis and pyroptosis enhanced the expression of proinflammatory cytokines and further exacerbated septic myocardial damage. However, irisin can inhibit the expression of TLR4 and its downstream signaling molecules and also lower the level of apoptosis and pyroptosis. Besides, similar results were also found in vitro model of LPS-induced H9c2 cardiomyocyte injury. In general, irisin suppressed inflammation, apoptosis, and pyroptosis by blocking the TLR4 and NLRP3 inflammasome signalings to mitigate myocardial dysfunction in sepsis.

Long-term mortality predictors of ICU fungaemia.

Bloodstream fungal infections have a high mortality rate. There is little data about the long-term mortality rate of fungaemia.This study aimed to explore the mortality of fungaemia and the influencing factors associated with death. In total, 204 intensive care unit (ICU) patients with fungaemia from Multi-parameter Intelligent Monitoring in Intensive Care-III (MIMIC-III) Database were studied. Age, gender, major underlying diseases, data about vital signs and blood test results were analysed to identify the predictors of the mortality and prognosis of fungaemia in ICU patients. Cox regression models were constructed, together with Kaplan-Meier survival curves. The 30-day, 1-year, 2-year, 3-year and 4-year mortality rates were 41.2%, 62.3%, 68.1%, 72.5% and 75%, respectively. Age (P ＜ 0.001, OR = 1.530; P ＜ 0.001, OR = 1.485)，serum bilirubin (P = 0.016, OR = 2.125；P = 0.001, OR = 1.748) and international normalised ratio (INR) (P = 0.001, OR = 2.642; P ＜ 0.001 OR = 2.065) were predictors of both the 30-day and 4-year mortality rates. Renal failure (P = 0.009, OR = 1.643) performed good in prediction of the 4-year mortality. The mortality of fungaemia is high. Age，the serum bilirubin and INR are good predictors of the 30-day and 4-year mortality rates of fungaemia. Renal failure has good performance in predicting the long-term mortality.

Deletion of TLR4 attenuates lipopolysaccharide-induced acute liver injury by inhibiting inflammation and apoptosis.

Septic acute liver injury is one of the leading causes of fatalities in patients with sepsis. Toll-like receptor 4 (TLR4) plays a vital role in response to lipopolysaccharide (LPS) challenge, but the mechanisms underlying TLR4 function in septic injury remains unclear. In this study, we investigated the role of TLR4 in LPS-induced acute liver injury (ALI) in mice with a focus on inflammation and apoptosis. Wild-type (WT) and TLR4-knockout (TLR4-/-) mice were challenged with LPS (4 mg/kg) for 6 h. TLR4 signaling cascade markers (TLR4, MyD88, and NF-κB), inflammatory markers (TNFα, IL-1ß, and IL-6), and apoptotic markers (Bax, Bcl-2, and caspase 3) were evaluated. We showed that LPS challenge markedly increased the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and other liver pathological changes in WT mice. In addition, LPS challenge elevated the levels of liver carbonyl proteins and serum inflammatory cytokines, upregulated the expression of TLR4, MyD88, and phosphorylated NF-κB in liver tissues. Moreover, LPS challenge significantly increased hepatocyte apoptosis, caspase 3 activity, and Bax level while suppressing Bcl-2 expression in liver tissues. These pathological changes were greatly attenuated in TLR4-/- mice. Similar pathological responses were provoked in primary hepatic Kupffer cells isolated from WT and TLR4-/- mice following LPS (1 µg/mL, 6 h) challenge. In summary, these results demonstrate that silencing of TLR4 attenuates LPS-induced liver injury through inhibition of inflammation and apoptosis via TLR4/MyD88/NF-κB signaling pathway. TLR4 deletion confers hepatoprotection against ALI induced by LPS, possibly by repressing macrophage inflammation and apoptosis.

Cardamonin protects against lipopolysaccharide-induced myocardial contractile dysfunction in mice through Nrf2-regulated mechanism.

In patients with sepsis, lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria triggers cardiac dysfunction and heart failure, but target therapy for septic cardiomyopathy remains unavailable. In this study we evaluated the beneficial effects of cardamonin (CAR), a flavone existing in Alpinia plant, on endotoxemia-induced cardiac dysfunction and the underlying mechanisms with focus on oxidative stress and apoptosis. Adult mice were exposed to LPS (4 mg/kg, i.p. for 6 h) prior to functional or biochemical assessments. CAR (20 mg/kg, p.o.) was administered to mice immediately prior to LPS challenge. We found that LPS challenge compromised cardiac contractile function, evidenced by compromised fractional shortening, peak shortening, maximal velocity of shortening/relengthening, enlarged LV end systolic diameter and prolonged relengthening in echocardiography, and induced apoptosis, overt oxidative stress (O2- production and reduced antioxidant defense) associated with inflammation, phosphorylation of NF-κB and cytosolic translocation of transcriptional factor Nrf2. These deteriorative effects were greatly attenuated or mitigated by CAR administration. However, H&E and Masson's trichrome staining analysis revealed that neither LPS challenge nor CAR administration significantly affected cardiomyocyte cross-sectional area and interstitial fibrosis. Mouse cardiomyocytes were treated with LPS (4 µg/mL) for 6 h in the absence or presence of CAR (10 µM) in vitro. We found that addition of CAR suppressed LPS-induced defect in cardiomyocyte shortening, which was nullified by the Nrf2 inhibitor ML-385 or the NF-κB activator prostratin. Taken together, our results suggest that CAR administration protects against LPS-induced cardiac contractile abnormality, oxidative stress, apoptosis, and inflammation through Nrf2- and NF-κB-dependent mechanism.

Irisin alleviates LPS-induced liver injury and inflammation through inhibition of NLRP3 inflammasome and NF-κB signaling.

Lipopolysaccharide (LPS) provokes severe inflammation and cell death in sepsis, with liver being the major affected organ. Up-to-date, neither the mechanism of action nor target treatment is readily available for LPS-induced liver injury. This study examined the effect of irisin, an endogenous hormonal peptide, on LPS-induced liver injury using animal and cell models, and the mechanism involved with a special focus on pyroptosis. Irisin is known to regulate glucose metabolism, inflammation, and immune response, while our earlier work denoted the anti-inflammatory and anti-apoptotic properties for irisin. Inflammatory factors and AST/ALT were also detected. Pyroptosis, apoptosis, and reactive oxygen species (ROS) were evaluated using PI staining, TUNEL staining, DCFH-DA fluorescence, and western blot, respectively. Our results indicated that irisin attenuated LPS-induced liver injury and release of inflammatory cytokines. Increased activity of NLRP3 inflammasome was discovered in LPS-challenged Raw264.7 cells, along with elevated levels of inflammation and apoptosis, the effects of which were mediated by activation of ROS and nuclear factor κB (NF-κB) signaling. These changes were reversed following irisin treatment. Our study demonstrated that irisin countered LPS-mediated liver injury via inhibiting apoptosis, NLRP3 inflammasome activation and NF-κB signaling. These findings revealed the role of irisin as a promising new anti-pyroptosis/apoptosis agent to reconcile the onset and progression of septic liver injury.

Parkin deficiency accentuates chronic alcohol intake-induced tissue injury and autophagy defects in brain, liver and skeletal muscle.

Alcoholism leads to organ injury including mitochondrial defect and apoptosis with evidence favoring a role for autophagy dysregulation in alcoholic damage. Parkin represents an autosomal recessive inherited gene for Parkinson's disease and an important member of selective autophagy for mitochondria. The association between Parkinson's disease and alcoholic injury remains elusive. This study aimed to examine the effect of parkin deficiency on chronic alcohol intake-induced organ injury in brain, liver and skeletal muscle (rectus femoris muscle). Adult parkin-knockout (PRK-/-) and wild-type mice were placed on Liber-De Carli alcohol liquid diet (4%) for 12 weeks prior to assessment of liver enzymes, intraperitoneal glucose tolerance, protein carbonyl content, apoptosis, hematoxylin and eosin morphological staining, and mitochondrial respiration (cytochrome c oxidase, NADH:cytochrome c reductase and succinate:cytochrome c reductase). Autophagy protein markers were monitored by western blot analysis. Our data revealed that chronic alcohol intake imposed liver injury as evidenced by elevated aspartate aminotransferase and alanine transaminase, glucose intolerance, elevated protein carbonyl formation, apoptosis, focal inflammation, necrosis, microvesiculation, autophagy/mitophagy failure and dampened mitochondrial respiration (complex IV, complexes I and III, and complexes II and III) in the brain, liver and rectus femoris skeletal muscle. Although parkin ablation itself did not generate any notable effects on liver enzymes, insulin sensitivity, tissue carbonyl damage, apoptosis, tissue morphology, autophagy or mitochondrial respiration, it accentuated alcohol intake-induced tissue damage, apoptosis, morphological change, autophagy/mitophagy failure and mitochondrial injury without affecting insulin sensitivity. These data suggest that parkin plays an integral role in the preservation against alcohol-induced organ injury, apoptosis and mitochondrial damage.

CD74 knockout protects against LPS-induced myocardial contractile dysfunction through AMPK-Skp2-SUV39H1-mediated demethylation of BCLB.

BACKGROUND AND PURPOSE: Lipopolysaccharides (LPS), an outer membrane component of Gram-negative bacteria, triggers myocardial anomalies in sepsis. Recent findings indicated a role for inflammatory cytokine MIF and its receptor, CD74, in septic organ injury, although little is known of the role of MIF-CD74 in septic cardiomyopathy. EXPERIMENTAL APPROACH: This study evaluated the impact of CD74 ablation on endotoxaemia-induced cardiac anomalies. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties were examined. KEY RESULTS: Our data revealed compromised cardiac function (lower fractional shortening, enlarged LV end systolic diameter, decreased peak shortening, maximal velocity of shortening/relengthening, prolonged duration of relengthening and intracellular Ca2+ mishandling) and ultrastructural derangement associated with inflammation, O2 - production, apoptosis, excess autophagy, phosphorylation of AMPK and JNK and dampened mTOR phosphorylation. These effects were attenuated or mitigated by CD74 knockout. LPS challenge also down-regulated Skp2, an F-box component of Skp1/Cullin/F-box protein-type ubiquitin ligase, while up-regulating that of SUV39H1 and H3K9 methylation of the Bcl2 protein BCLB. These effects were reversed by CD74 ablation. In vitro study revealed that LPS facilitated GFP-LC3B formation and cardiomyocyte defects. These effects were prevented by CD74 ablation. Interestingly, the AMPK activator AICAR, the autophagy inducer rapamycin and the demethylation inhibitor difenoconazole inhibited the effects of CD74 ablation against LPS-induced cardiac dysfunction, while the SUV39H1 inhibitor chaetocin or methylation inhibitor 5-AzaC ameliorated LPS-induced GFP-LC3B formation and cardiomyocyte contractile dysfunction. CONCLUSION AND IMPLICATIONS: Our data suggested that CD74 ablation protected against LPS-induced cardiac anomalies, O2 - production, inflammation and apoptosis through suppression of autophagy in a Skp2-SUV39H1-mediated mechanism.

Mitochondrial Injury and Targeted Intervention in Septic Cardiomyopathy.

BACKGROUND: Sepsis and septic shock are known to prompt multiple organ failure including cardiac contractile dysfunction, which is typically referred to as septic cardiomyopathy. Among various theories postulated for the etiology of septic cardiomyopathy, mitochondrial injury (both morphology and function) in the heart is perceived as the main culprit for reduced myocardial performance and ultimately heart failure in the face of sepsis. METHODS: Over the past decades, ample of experimental and clinical work have appeared, focusing on myocardial mitochondrial changes and related interventions in septic cardiomyopathy. RESULTS AND CONCLUSION: Here we will briefly summarize the recent experimental and clinical progress on myocardial mitochondrial morphology and function in sepsis, and discuss possible underlying mechanisms, as well as the contemporary interventional options.

Cardiac-specific overexpression of metallothionein attenuates L-NAME-induced myocardial contractile anomalies and apoptosis.

Hypertension contributes to the high cardiac morbidity and mortality. Although oxidative stress plays an essential role in hypertensive heart diseases, the mechanism remains elusive. Transgenic mice with cardiac overexpression of metallothionein, a heavy metal-binding scavenger, were challenged with NG -nitro-L-arginine methyl ester (L-NAME) for 14 days prior to measurement of myocardial contractile and intracellular Ca2+ anomalies as well as cell signalling mechanisms using Western blot and immunofluorescence analysis. L-NAME challenge elicited hypertension, macrophage infiltration, oxidative stress, inflammation and cardiac dysfunction manifested as increased proinflammatory macrophage marker F4/80, interleukin-1ß (IL-1ß), intracellular O2- production, LV end systolic and diastolic diameters as well as depressed fractional shortening. L-NAME treatment reduced mitochondrial membrane potential (MMP), impaired cardiomyocyte contractile and intracellular Ca2+ properties as evidenced by suppressed peak shortening, maximal velocity of shortening/relengthening, rise in intracellular Ca2+ , along with elevated baseline and peak intracellular Ca2+ . These unfavourable mechanical changes and decreased MMP (except blood pressure and macrophage infiltration) were alleviated by overexpression of metallothionein. Furthermore, the apoptosis markers including BAD, Bax, Caspase 9, Caspase 12 and cleaved Caspase 3 were up-regulated while the anti-apoptotic marker Bcl-2 was decreased by L-NAME treatment. Metallothionein transgene reversed L-NAME-induced changes in Bax, Bcl-2, BAD phosphorylation, Caspase 9, Caspase 12 and cleaved Caspase 3. Our results suggest that metallothionein protects against L-NAME-induced myocardial contractile anomalies in part through inhibition of apoptosis.

Obesity is a common soil for premature cardiac aging and heart diseases - Role of autophagy.

The advance in medical technology and healthcare has dramatically improved the average human lifespan. One of the consequences for longevity is the high prevalence of aging-related chronic disorders such as cardiovascular diseases, cancer and metabolic abnormalities. As the composition of aging population is raising in western countries, heart failure remains the number one cause of death with a more severe impact in the elderly. Obesity and aging are the most critical risk factors for increased susceptibility to heart failure in developing and developed countries. Numerous population-based and experimental data have depicted a close relationship between the age-related diseases and obesity. There is an overall agreement that obesity is causally linked to the development of cardiovascular disorders and severe premature cardiac aging. Accumulating evidence indicates that autophagy plays an important role in obesity, cardiac aging and diseases. In this review, we will focus on the role of autophagy in obesity-related cardiac aging and diseases, and how it regulates age-dependent changes in the heart.

Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway.

Irisin plays a protective effect in acute and chronic myocardial damage, but its role in septic cardiomyopathy is unclear. The aim of our study was to explore the in vivo and in vitro effects of irisin using an LPS-induced septic cardiomyopathy model. Our results demonstrated that irisin treatment attenuated LPS-mediated cardiomyocyte death and myocardial dysfunction. At the molecular level, LPS application was associated with mitochondrial oxidative injury, cardiomyocyte ATP depletion and caspase-related apoptosis activation. In contrast, the irisin treatment sustained mitochondrial function by inhibiting DRP1-related mitochondrial fission and the reactivation of mitochondrial fission impaired the protective action of irisin on inflammation-attacked mitochondria and cardiomyocytes. Additionally, we found that irisin modulated DRP1-related mitochondrial fission through the JNK-LATS2 signaling pathway. JNK activation and/or LATS2 overexpression abolished the beneficial effects of irisin on LPS-mediated mitochondrial stress and cardiomyocyte death. Altogether, our results illustrate that LPS-mediated activation of DRP1-related mitochondrial fission through the JNK-LATS2 pathway participates in the pathogenesis of septic cardiomyopathy. Irisin could be used in the future as an effective therapy for sepsis-induced myocardial depression because it corrects DRP1-related mitochondrial fission and normalizes the JNK-LATS2 signaling pathway.

Role of autophagy in inherited metabolic and endocrine myopathies.

The prevalence of cardiometabolic disease has reached an exponential rate of rise over the last decades owing to high fat/high caloric diet intake and satiety life style. Although the presence of dyslipidemia, insulin resistance, hypertension and obesity mainly contributes to the increased incidence of cardiometabolic diseases, population-based, clinical and genetic studies have revealed a rather important role for inherited myopathies and endocrine disorders in the ever-rising metabolic anomalies. Inherited metabolic and endocrine diseases such as glycogen storage and lysosomal disorders have greatly contributed to the overall prevalence of cardiometabolic diseases. Recent evidence has demonstrated an essential role for proteotoxicity due to autophagy failure and/or dysregulation in the onset of inherited metabolic and endocrine disorders. Given the key role for autophagy in the degradation and removal of long-lived or injured proteins and organelles for the maintenance of cellular and organismal homeostasis, this mini-review will discuss the potential contribution of autophagy dysregulation in the pathogenesis of inherited myopathies and endocrine disorders, which greatly contribute to an overall rise in prevalence of cardiometabolic disorders. Molecular, clinical, and epidemiological aspects will be covered as well as the potential link between autophagy and metabolic anomalies thus target therapy may be engaged for these comorbidities.