Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications.

The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy," which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.

SGLT2 inhibitor empagliflozin alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease.

Recent evidence shows a close link between Parkinson's disease (PD) and cardiac dysfunction with limited treatment options. Mitophagy plays a crucial role in the control of mitochondrial quantity, metabolic reprogramming and cell differentiation. Mutation of the mitophagy protein Parkin is directly associated with the onset of PD. Parkin-independent receptor-mediated mitophagy is also documented such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and FUN14 domain containing 1 (FUNDC1) for receptor-mediated mitophagy. In this study we investigated cardiac function and mitophagy including FUNDC1 in PD patients and mouse models, and evaluated the therapeutic potential of a SGLT2 inhibitor empagliflozin. MPTP-induced PD model was established. PD patients and MPTP mice not only displayed pronounced motor defects, but also low plasma FUNDC1 levels, as well as cardiac ultrastructural and geometric anomalies (cardiac atrophy, interstitial fibrosis), functional anomalies (reduced E/A ratio, fractional shortening, ejection fraction, cardiomyocyte contraction) and mitochondrial injury (ultrastructural damage, UCP2, PGC1α, elevated mitochondrial Ca2+ uptake proteins MCU and VDAC1, and mitochondrial apoptotic protein calpain), dampened autophagy, FUNDC1 mitophagy and apoptosis. By Gene set enrichment analysis (GSEA), we found overtly altered glucose transmembrane transport in the midbrains of MPTP-treated mice. Intriguingly, administration of SGLT2 inhibitor empagliflozin (10 mg/kg, i.p., twice per week for 2 weeks) in MPTP-treated mice significantly ameliorated myocardial anomalies (with exception of VDAC1), but did not reconcile the motor defects or plasma FUNDC1. FUNDC1 global knockout (FUNDC1-/- mice) did not elicit any phenotype on cardiac geometry or function in the absence or presence of MPTP insult, but it nullified empagliflozin-caused cardioprotection against MPTP-induced cardiac anomalies including remodeling (atrophy and fibrosis), contractile dysfunction, Ca2+ homeostasis, mitochondrial (including MCU, mitochondrial Ca2+ overload, calpain, PARP1) and apoptotic anomalies. In neonatal and adult cardiomyocytes, treatment with PD neurotoxin preformed fibrils of α-synuclein (PFF) caused cytochrome c release and cardiomyocyte mechanical defects. These effects were mitigated by empagliflozin (10 µM) or MCU inhibitor Ru360 (10 µM). MCU activator kaempferol (10 µM) or calpain activator dibucaine (500 µM) nullified the empagliflozin-induced beneficial effects. These results suggest that empagliflozin protects against PD-induced cardiac anomalies, likely through FUNDC1-mediated regulation of mitochondrial integrity.

ER stress and inflammation crosstalk in obesity.

The endoplasmic reticulum (ER) governs the proper folding of polypeptides and proteins through various chaperones and enzymes residing within the ER organelle. Perturbation in the ER folding process ensues when overwhelmed protein folding exceeds the ER handling capacity, leading to the accumulation of misfolded/unfolded proteins in the ER lumen-a state being referred to as ER stress. In turn, ER stress induces a gamut of signaling cascades, termed as the "unfolded protein response" (UPR) that reinstates the ER homeostasis through a panel of gene expression modulation. This type of UPR is usually deemed "adaptive UPR." However, persistent or unresolved ER stress hyperactivates UPR response, which ultimately, triggers cell death and inflammatory pathways, termed as "maladaptive/terminal UPR." A plethora of evidence indicates that crosstalks between ER stress (maladaptive UPR) and inflammation precipitate obesity pathogenesis. In this regard, the acquisition of the mechanisms linking ER stress to inflammation in obesity might unveil potential remedies to tackle this pathological condition. Herein, we aim to elucidate key mechanisms of ER stress-induced inflammation in the context of obesity and summarize potential therapeutic strategies in the management of obesity through maneuvering ER stress and ER stress-associated inflammation.

CD74 ablation rescues type 2 diabetes mellitus-induced cardiac remodeling and contractile dysfunction through pyroptosis-evoked regulation of ferroptosis.

Type 2 diabetes mellitus (T2D) contributes to sustained inflammation and myopathic changes in the heart although the precise interplay between the two remains largely unknown. This study evaluated the impact of deficiency in CD74, the cognate receptor for the regulatory cytokine macrophage migration inhibitory factor (MIF), in T2D-induced cardiac remodeling and functional responses, and cell death domains involved. WT and CD74-/- mice were fed a high fat diet (60% calorie from fat) for 8 weeks prior to injection of streptozotocin (STZ, 35 mg/kg, i.p., 3 consecutive days) and were maintained for another 8 weeks. KEGG analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis in T2D mouse hearts. T2D patients displayed elevated plasma MIF levels. Murine T2D exerted overt global metabolic derangements, cardiac remodeling, contractile dysfunction, apoptosis, pyroptosis, ferroptosis and mitochondrial dysfunction, ablation of CD74 attenuated T2D-induced cardiac remodeling, contractile dysfunction, various forms of cell death and mitochondrial defects without affecting global metabolic defects. CD74 ablation rescued T2D-evoked NLRP3-Caspase1 activation and oxidative stress but not dampened autophagy. In vitro evidence depicted that high glucose/high fat (HGHF) compromised cardiomyocyte function and promoted lipid peroxidation, the effects were ablated by inhibitors of NLRP3, pyroptosis, and ferroptosis but not by the mitochondrial targeted antioxidant mitoQ. Recombinant MIF mimicked HGHF-induced lipid peroxidation, GSH depletion and ferroptosis, the effects of which were reversed by inhibitors of MIF, NLRP3 and pyroptosis. Taken together, these data suggest that CD74 ablation protects against T2D-induced cardiac remodeling and contractile dysfunction through NLRP3/pyroptosis-mediated regulation of ferroptosis.

Chinese wheat mosaic virus-derived vsiRNA-20 can regulate virus infection in wheat through inhibition of vacuolar- (H+ )-PPase induced cell death.

Vacuolar (H+ )-PPases (VPs), are key regulators of active proton (H+ ) transport across membranes using the energy generated from PPi hydrolysis. The VPs also play vital roles in plant responses to various abiotic stresses. Their functions in plant responses to pathogen infections are unknown. Here, we show that TaVP, a VP of wheat (Triticum aestivum) is important for wheat resistance to Chinese wheat mosaic virus (CWMV) infection. Furthermore, overexpression of TaVP in plants induces the activity of PPi hydrolysis, leading to plants cell death. A virus-derived small interfering RNA (vsiRNA-20) generated from CWMV RNA1 can regulate the mRNA accumulation of TaVP in wheat. The accumulation of vsiRNA-20 can suppress cell death induced by TaVP in a dosage-dependent manner. Moreover, we show that the accumulation of vsiRNA-20 can affect PPi hydrolysis and the concentration of H+ in CWMV-infected wheat cells to create a more favorable cellular environment for CWMV replication. We propose that vsiRNA-20 regulates TaVP expression to prevent cell death and to maintain a weak alkaline environment in cytoplasm to enhance CWMV infection in wheat. This finding may be used as a novel strategy to minimize virus pathogenicity and to develop new antiviral stratagems.

Aldehyde Dehydrogenase 2 (ALDH2) and Aging: Is There a Sensible Link?

Aging is a complex irreversible biological process associated with increased prevalence of chronic disease and high healthcare burden. Several theories have been proposed for the biology of aging including free radical accumulation, DNA damage, apoptosis, telomere shortening, autophagy failure, and disturbed autonomic response. Aging is also closely associated with progressive deterioration of cardiovascular and neurological functions. Linkage, genome-wide association (GWAS), and next-generation sequencing analysis have confirmed a number of susceptibility loci for aging, in particular, Alzheimer's disease. Recent evidence from our group and others also revealed a tie between genetic mutation of mitochondrial aldehyde dehydrogenase (ALDH2) and life span as well as cardiovascular aging. ALDH2 represents the single most gene with the greatest number of human genetic polymorphism and is deemed an important enzyme for detoxification of reactive aldehydes. Here, we will briefly review the tie between ALDH2 and cardiovascular aging process. While recent work on ALDH2 research has broadened the pathogenic mechanisms of ALDH2 mutation or deficiency, therapeutic potential targeting ALDH2 in the elderly still remains debatable.

The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis.

Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5-MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury.

Ablation of Akt2 rescues chronic caloric restriction-provoked myocardial remodeling and dysfunction through a CDK1-mediated regulation of mitophagy.

Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca2+ capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca2+ governing components Na+-Ca2+ exchanger, phosphorylation of SERCA2a, mTOR (Ser2481) and ULK1 (Ser757), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser555), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner.

Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis.

Mitochondrial DNA (mtDNA) released through protein oligomers, such as voltage-dependent anion channel 1 (VDAC1), triggers innate immune activation and thus contributes to liver fibrosis. Here, we investigated the role of Parkin, an important regulator of mitochondria, and its regulation of VDAC1-mediated mtDNA release in liver fibrosis. The circulating mitochondrial DNA (mtDNA) and protein levels of liver Parkin and VDAC1 were upregulated in patients with liver fibrosis. A 4-week CCl4 challenge induced release of mtDNA, activation of STING signaling, a decline in autophagy, and apoptosis in mouse livers, and the knockout of Parkin aggravated these effects. In addition, Parkin reduced mtDNA release and prevented VDAC1 oligomerization in a manner dependent on its E3 activity in hepatocytes. We found that site-specific ubiquitination of VDAC1 at lysine 53 by Parkin interrupted VDAC1 oligomerization and prevented mtDNA release into the cytoplasm under stress. The ubiquitination-defective VDAC1 K53R mutant predominantly formed oligomers that resisted suppression by Parkin. Hepatocytes expressing VDAC1 K53R exhibited mtDNA release and thus activated the STING signaling pathway in hepatic stellate cells, and this effect could not be abolished by Parkin. We propose that the ubiquitination of VDAC1 at a specific site by Parkin confers protection against liver fibrosis by interrupting VDAC1 oligomerization and mtDNA release.

Syntaxin17 contributes to obesity cardiomyopathy through promoting mitochondrial Ca2+ overload in a Parkin-MCUb-dependent manner.

OBJECTIVE: Uncorrected obesity is accompanied by unfavorable structural and functional changes in the heart, known as obesity cardiomyopathy. Recent evidence has revealed a crucial role for mitochondria-associated endoplasmic reticulum membranes (MAMs) in obesity-induced cardiac complication. Syntaxin 17 (STX17) serves as a scaffolding molecule localized on MAMs although its role in obesity heart complication remains elusive. METHODS AND MATERIALS: This study examined the role of STX17 in MAMs and mitochondrial Ca2+ homeostasis in HFD-induced obesity cardiomyopathy using tamoxifen-induced cardiac-specific STX17 knockout (STX17cko) and STX17 overexpression mice using intravenously delivered recombinant adeno-associated virus serotype-9 (AAV9-cTNT-STX17). RESULTS: STX17 levels were significantly elevated in plasma from obese patients and heart tissues of HFD-fed mice. Our data revealed that cardiac STX17 knockout alleviated cardiac remodeling and dysfunction in obese hearts without eliciting any notable effect itself, while STX17 overexpression aggravated cardiac dysfunction in obese mice. STX17 deletion and STX17 overexpression annihilated and aggravated, respectively, HFD-induced oxidative stress (O2- production) and mitochondrial injury in the heart. Furthermore, STX17 transfection facilitated obesity-induced MAMs formation in cardiomyocytes and evoked excess mitochondrial Ca2+ influx, dependent upon interaction with mitochondrial Ca2+ uniporter dominant negative ß (MCUb) through Habc domain. Our data also suggested that STX17 promoted ubiquitination and degradation of MCUb through the E3 ligase parkin in the face of palmitate challenging. CONCLUSION: Taken together, our results identified a novel role for STX17 in facilitating obesity-induced MAMs formation, and subsequently mitochondrial Ca2+ overload, mitochondrial O2- accumulation, lipid peroxidation, resulting in cardiac impairment. Our findings denoted therapeutic promises of targeting STX17 in obesity.

Syntaxin 17 Protects Against Heart Failure Through Recruitment of CDK1 to Promote DRP1-Dependent Mitophagy.

Mitochondrial dysfunction is suggested to be a major contributor for the progression of heart failure (HF). Here we examined the role of syntaxin 17 (STX17) in the progression of HF. Cardiac-specific Stx17 knockout manifested cardiac dysfunction and mitochondrial damage, associated with reduced levels of p(S616)-dynamin-related protein 1 (DRP1) in mitochondria-associated endoplasmic reticulum membranes and dampened mitophagy. Cardiac STX17 overexpression promoted DRP1-dependent mitophagy and attenuated transverse aortic constriction-induced contractile and mitochondrial damage. Furthermore, STX17 recruited cyclin-dependent kinase-1 through its SNARE domain onto mitochondria-associated endoplasmic reticulum membranes, to phosphorylate DRP1 at Ser616 and promote DRP1-mediated mitophagy upon transverse aortic constriction stress. These findings indicate the potential therapeutic benefit of targeting STX17 in the mitigation of HF.

TBC1D15-Drp1 interaction-mediated mitochondrial homeostasis confers cardioprotection against myocardial ischemia/reperfusion injury.

OBJECTIVE: Mitochondria are essential for myocardial ischemia/reperfusion (I/R) injury. TBC domain family member 15 (TBC1D15) participates in the regulation of mitochondrial homeostasis although its role remains elusive in I/R injury. METHODS AND MATERIALS: This study examined the role of TBC1D15 in mitochondrial homeostasis under myocardial I/R injury using inducible cardiac-specific TBC1D15 knockin (TBC1D15CKI) and knockout (TBC1D15CKO) mice. RESULTS: TBC1D15 mRNA/protein levels were downregulated in human ischemic cardiomyopathy samples, mouse I/R hearts and neonatal mouse cardiomyocytes with H/R injury, consistent with scRNA sequencing finding from patients with coronary heart disease. Cardiac-specific knockin of TBC1D15 attenuated whereas cardiac-specific knockout of TBC1D15 overtly aggravated I/R-induced cardiomyocyte apoptosis and cardiac dysfunction. TBC1D15CKI mice exhibited reduced mitochondrial damage and mitochondrial fragmentation following myocardial I/R injury, while TBC1D15CKO mice displayed opposite results. TBC1D15 preserved mitochondrial function evidenced by safeguarding MMP and oxygen consumption capacity, antagonizing ROS accumulation and cytochrome C release, which were nullified by TBC1D15 knockdown. Time-lapse confocal microscopy revealed that TBC1D15 activated asymmetrical mitochondrial fission through promoting mitochondria-lysosome contacts untethering in NMCMs under H/R injury, whereas overexpression of TBC1D15 mutants (R400K and ∆231-240) failed to regulate asymmetrical fission and knockdown of TBC1D15 slowed down asymmetrical fission. Moreover, TBC1D15-offered benefits were mitigated by knockdown of Fis1 and Drp1. Mechanistically, TBC1D15 recruited Drp1 to mitochondria-lysosome contact sites via direct interaction with Drp1 through its C terminus (574-624) domain. Interfering with interaction between TBC1D15 and Drp1 abrogated asymmetrical mitochondrial fission and mitochondrial function. Cardiac phenotypes of TBC1D15CKO mice upon I/R injury were rescued by adenovirus-mediated overexpression of wild-type but not mutants (R400K, ∆231-240 and ∆574-624) TBC1D15. CONCLUSIONS: TBC1D15 ameliorated I/R injury through a novel modality to preserve mitochondrial homeostasis where mitochondria-lysosome contacts (through the TBC1D15/Fis1/RAB7 cascade) regulate asymmetrical mitochondrial fission (TBC1D15/Drp1 interaction), suggesting promises of targeting TBC1D15 in the management of myocardial I/R injury.

Parkin Insufficiency Accentuates High-Fat Diet-Induced Cardiac Remodeling and Contractile Dysfunction Through VDAC1-Mediated Mitochondrial Ca2+ Overload.

Mitochondrial Ca2+ overload contributes to obesity cardiomyopathy, yet mechanisms that directly regulate it remain elusive. The authors investigated the role of Parkin on obesity-induced cardiac remodeling and dysfunction in human hearts and a mouse model of 24-week high-fat diet (HFD) feeding. Parkin knockout aggravated HFD-induced cardiac remodeling and dysfunction, mitochondrial Ca2+ overload, and apoptosis without affecting global metabolism, blood pressure, and aortic stiffness. Parkin deficiency unmasked HFD-induced decline in voltage-dependent anion channel (VDAC) type 1 degradation through the ubiquitin-proteasome system but not other VDAC isoforms or mitochondrial Ca2+ uniporter complex. These data suggest that Parkin-mediated proteolysis of VDAC type 1 is a promising therapeutic target for obesity cardiomyopathy.

Deletion of the E3 ubiquitin ligase, Parkin, exacerbates chronic alcohol intake-induced cardiomyopathy through an Ambra1-dependent mechanism.

BACKGROUND AND PURPOSE: Chronic alcohol consumption contributes to contractile dysfunction and unfavourable geometric changes in myocardium, accompanied by altered autophagy and disturbed mitochondrial homeostasis. The E3 ubiquitin ligase Parkin encoded by PARK2 gene maintains a fundamental role in regulating mitophagy and mitochondrial homeostasis, although little is known of its role in the aetiology of alcoholic cardiomyopathy. Here we assessed the effects of Parkin deletion in chronic alcohol-evoked cardiotoxicity. EXPERIMENTAL APPROACH: Following alcohol (4%) or control diet intake for 8 weeks, adult male wild-type (WT) and PARK2 knockout (Parkin-/- ) mice were examined using echocardiography. Cardiomyocyte mechanical properties, morphology of myocardium, and mitochondrial damage were also evaluated. Autophagy and mitophagy levels were assessed by LC3B and GFP-LC3 puncta, and lysosome-dependent autophagic flux was scrutinized using GFP-mRFP-LC3 puncta and Bafilomycin A1 treatment. KEY RESULTS: Chronic alcohol exposure provoked unfavourable geometric changes in myocardium and led to mitochondrial dysfunction and cardiac contractile defects, effects further exacerbated by Parkin knockout. Chronic alcohol exposure provoked autophagy and PINK1/Parkin-mediated mitophagy without affecting lysosome-dependent autophagic flux, the effects of which were diminished by Parkin deletion. Parkin adenovirus infection in neonatal rat cardiomyocytes further increased autophagy and protected against alcohol-induced myocardial injury, effects blocked by siRNA for Ambra1 (Autophagy and Beclin1 regulator 1). Immunofluorescence staining and co-immunoprecipitation assays showed interactions between Parkin and Ambra1. CONCLUSIONS AND IMPLICATIONS: Parkin was essential for cardiac homeostasis in alcohol challenge, accompanied by increased autophagy/mitophagy and maintenance of mitochondrial integrity through its interaction with Ambra1.

Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism.

High fat diet intake contributes to undesired cardiac geometric and functional changes although the underlying mechanism remains elusive. Akt and AMPK govern to cardiac homeostasis. This study examined the impact of deletion of Akt2 (main cardiac isoform of Akt) and AMPKα2 on high fat diet intake-induced cardiac remodeling and contractile anomalies and mechanisms involved. Cardiac geometry, contractile, and intracellular Ca2+ properties were evaluated using echocardiography, IonOptix® edge-detection and fura-2 techniques in wild-type (WT) and Akt2-AMPK double knockout (DKO) mice receiving low fat (LF) or high fat (HF) diet for 4 months. Our results revealed that fat diet intake elicit obesity, cardiac remodeling (hypertrophy, LV mass, LVESD, and cross-sectional area), contractile dysfunction (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, and intracellular Ca2+ handling), ultrastructural disarray, apoptosis, O2-, inflammation, dampened autophagy and mitophagy. Although DKO did not affect these parameters, it accentuated high fat diet-induced cardiac remodeling and contractile anomalies. High fat intake upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and STING phosphorylation while suppressing phosphorylation of ULK1 (Ser757 and Ser777), with a more pronounced effect in DKO mice. In vitro data revealed that inhibition of cGAS and STING using PF-06928215 and Astin C negated palmitic acid-induced cardiomyocyte contractile dysfunction. Biological function analysis for all differentially expressed genes (DEGs) depicted that gene ontology terms associated with Akt and AMPK signaling processes were notably changed in high fat-fed hearts. Our data indicate that Akt2-AMPK ablation accentuated high fat diet-induced cardiac anomalies possibly through a cGAS-STING-mechanism.

Mitophagy, Mitochondrial Dynamics, and Homeostasis in Cardiovascular Aging.

Biological aging is an inevitable and independent risk factor for a wide array of chronic diseases including cardiovascular and metabolic diseases. Ample evidence has established a pivotal role for interrupted mitochondrial homeostasis in the onset and development of aging-related cardiovascular anomalies. A number of culprit factors have been suggested in aging-associated mitochondrial anomalies including oxidative stress, lipid toxicity, telomere shortening, metabolic disturbance, and DNA damage, with recent findings revealing a likely role for compromised mitochondrial dynamics and mitochondrial quality control machinery such as autophagy. Mitochondria undergo consistent fusion and fission, which are crucial for mitochondrial homeostasis and energy adaptation. Autophagy, in particular, mitochondria-selective autophagy, namely, mitophagy, refers to a highly conservative cellular process to degrade and clear long-lived or damaged cellular organelles including mitochondria, the function of which gradually deteriorates with increased age. Mitochondrial homeostasis could be achieved through a cascade of independent but closely related processes including fusion, fission, mitophagy, and mitochondrial biogenesis. With improved health care and increased human longevity, the ever-rising aging society has imposed a high cardiovascular disease prevalence. It is thus imperative to understand the role of mitochondrial homeostasis in the regulation of lifespan and healthspan. Targeting mitochondrial homeostasis should offer promising novel therapeutic strategies against aging-related complications, particularly cardiovascular diseases.

Physical Exercise and Selective Autophagy: Benefit and Risk on Cardiovascular Health.

Physical exercise promotes cardiorespiratory fitness, and is considered the mainstream of non-pharmacological therapies along with lifestyle modification for various chronic diseases, in particular cardiovascular diseases. Physical exercise may positively affect various cardiovascular risk factors including body weight, blood pressure, insulin sensitivity, lipid and glucose metabolism, heart function, endothelial function, and body fat composition. With the ever-rising prevalence of obesity and other types of metabolic diseases, as well as sedentary lifestyle, regular exercise of moderate intensity has been indicated to benefit cardiovascular health and reduce overall disease mortality. Exercise offers a wide cadre of favorable responses in the cardiovascular system such as improved dynamics of the cardiovascular system, reduced prevalence of coronary heart diseases and cardiomyopathies, enhanced cardiac reserve capacity, and autonomic regulation. Ample clinical and experimental evidence has indicated an emerging role for autophagy, a conservative catabolism process to degrade and recycle cellular organelles and nutrients, in exercise training-offered cardiovascular benefits. Regular physical exercise as a unique form of physiological stress is capable of triggering adaptation while autophagy in particular selective autophagy seems to be permissive to such cardiovascular adaptation. Here in this mini-review, we will summarize the role for autophagy in particular mitochondrial selective autophagy namely mitophagy in the benefit versus risk of physical exercise on cardiovascular function.

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We investigated the variation of denitrifying communities in rice rhizosphere at tillering and booting stages in comparison with bulk soils with a pot experiment. The techniques of quantitative polymerase chain reaction (qPCR) and terminal restriction fragment length polymorphism (T-RFLP) were used to measure the abundance and community composition of denitrifiers (narG and nosZ), respectively. The results showed that the potential denitrification activity in the rhizosphere at tillering stage was significantly lower than bulk soils. No significant difference was detected between the rhizosphere and bulk soils at booting stage. The abundance of both narG- and nosZ-containing denitrifying bacteria was significantly higher in rhizosphere than in bulk soils at both tillering and booting stages. In comparison with narG-containing community, community composition and diversity of nosZ-containing bacteria were more sensitive to rice growth. In conclusion, the exudates of rice could induce significantly more denitrifying bacteria in rhizosphere, whose denitrifying activities were related to growth stage of rice. At the period with strong growth, the secretion of roots showed clear restriction to the functions of rhizospheric denitrifiers compared to booting stage.

A furoviral replicase recruits host HSP70 to membranes for viral RNA replication.

Many host factors have been identified to be involved in viral infection. However, although furoviruses cause important diseases of cereals worldwide, no host factors have yet been identified that interact with furoviral genes or participate in the viral infection cycle. In this study, both TaHSP70 and NbHSP70 were up-regulated in Chinese wheat mosaic furovirus (CWMV)-infected plants. Their overexpression and inhibition were correlated with the accumulation of viral genomic RNAs, suggesting that the HSP70 genes could be necessary for CWMV infection. The subcellular distributions of TaHSP70 and NbHSP70 were significantly affected by CWMV infection or by infiltration of RNA1 alone. Further assays showed that the viral replicase encoded by CWMV RNA1 interacts with both TaHSP70 and NbHSP70 in vivo and vitro and that its region aa167-333 was responsible for the interaction. Subcellular assays showed that the viral replicase could recruit both TaHSP70 and NbHSP70 from the cytoplasm or nucleus to the granular aggregations or inclusion-like structures on the intracellular membrane system, suggesting that both HSP70s may be recruited into the viral replication complex (VRC) to promote furoviral replication. This is the first host factor identified to be involved in furoviral infection, which extends the list and functional scope of HSP70 chaperones.

[Effects of Fertilization on Soil Microbial Abundance and Community Structure at DNA and cDNA Levels in Paddy Soils].

Fertilizer applications have important effects on soil microbial abundance and community structure. In this study, total soil microbial DNA and RNA were directly extracted from paddy soils of N0 (control treatment, no nitrogen fertilizer), NPK (balanced fertilization), NPK+LS (balanced fertilization with additional 3.0 t·hm-2 rice straw incorporation) and NPK+HS (balanced fertilization with additional 6.0 t·hm-2 rice straw incorporation) treatments in a long-term fertilization experiment of double rice cropping system in Changsha County, Hunan Province. Soil bacteria community structures were evaluated by analyzing the 16S rRNA gene fragments at DNA and cDNA levels with Terminal Restriction Fragment Length Polymorphism (T-RFLP) and quantitative PCR techniques. Balancing fertilization with chemical fertilizers and rice straw incorporation significantly changed the composition of bulk (DNA-based) and potentially active (mRNA-based) soil bacterial community as shown in T-RFLP profiles, and also reduced the bulk soil microbial diversity, but not the potentially active ones, as compared with the control treatment. The DNA-based abundance of 16S rRNA gene was on average 377 times as many as the m-RNA based population size. Compared to N0,balanced fertilization with rice straw incorporation (NPK+LS and NPK+HS) increased the bulk and active copy numbers of 16S rRNA gene, but not for balanced fertilization (NPK). The abundance and microbial community structure were not significantly different between the NPK+LS and NPK+HS treatments. Redundancy analysis (RDA) showed that soil ammonium was the key environmental factor determining the bulk and active soil microbial community structure among the treatments. In conclusion, the effect of fertilization on soil microbial abundance and community structure could be indicated at both DNA and cDNA levels; the cDNA information could better reflect the adaptability of bacterial community to the environmental stress.