Cholinergic drugs reduce metabolic inflammation and diabetic myocardial injury by regulating the gut bacterial component lipopolysaccharide-induced ERK/Egr-1 pathway.

Autonomic imbalance and metabolic inflammation are important pathological processes in diabetic cardiomyopathy. Gut microbiota dysbiosis and increased levels of bacterial component lipopolysaccharide (LPS) are associated with diabetic myocardial injury, but the mechanism by which gut microbes affect metabolic inflammation and cardiac injury remains unclear. We determined whether pyridostigmine (PYR), which inhibits cholinesterase to improve vagal activity, could regulate the disordered gut microbiota and attenuate gut barrier dysfunction, metabolic endotoxemia, and inflammation in diabetes. Db/db mice exhibited high blood glucose levels, insulin resistance, low vagal activity, and diabetic myocardial injury. Db/db mice also exhibited gut microbiota perturbations and subsequent disruption of gut barrier function, resulting in an influx of LPS, metabolic endotoxemia, and inflammation. PYR ameliorated the dysregulated glucose and lipid metabolism, modulated the overall structure of the gut microbiota, selectively enhanced the abundance of anti-inflammatory bacteria, and reduced the abundance of proinflammatory and potentially pathogenic bacteria in db/db mice. Importantly, PYR enhanced vagal activity, restored gut microbiota homeostasis, and alleviated gut barrier dysfunction. Therefore, the LPS-induced extracellular signal-regulated kinase (ERK)/early growth response-1 (Egr-1) pathway and consequent metabolic inflammation were inhibited, and eventually, cardiac hypertrophy, fibrosis, oxidative stress, and dysfunction were ameliorated in db/db mice. In vitro cardiomyocyte injury was induced by exposing primary neonatal rat ventricular cardiomyocytes to high glucose (HG) and LPS. In vitro analyses showed that HG + LPS induced ERK1/2 phosphorylation, Egr-1 expression, inflammation, and cell apoptosis, which were inhibited by acetylcholine (ACh). Alpha 7 nicotinic ACh receptor but not muscarinic 2 ACh receptor plays an important role in ACh-mediated anti-inflammatory effects and inhibiting the ERK/Egr-1 pathway in HG + LPS-administered neonatal rat ventricular cardiomyocytes. PYR and ACh ameliorated diabetic myocardial injury by inhibiting the LPS-induced ERK/Egr-1 pathway and metabolic inflammation. The vagus-gut-heart axis has provided new insights into the complex mechanisms of diabetes and offers novel therapeutic targets.

Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.

Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases.

Mitochondrial homeostasis and redox status in cardiovascular diseases: Protective role of the vagal system.

Mitochondria participate in essential cellular functions, including energy production, metabolism, redox homeostasis regulation, intracellular Ca2+ handling, apoptosis, and cell fate determination. Disruption of mitochondrial homeostasis under pathological conditions results in mitochondrial reactive oxygen species (ROS) generation and energy insufficiency, which further disturb mitochondrial and cellular homeostasis in a deleterious loop. Mitochondrial redox status has therefore become a potential target for therapy against cardiovascular diseases. In this review, we highlight recent progress in determining the roles of mitochondrial processes in regulating mitochondrial redox status, including mitochondrial dynamics (fusion-fission pathways), mitochondrial cristae remodeling, mitophagy, biogenesis, and mitochondrion-organelle interactions (endoplasmic reticulum-mitochondrion interactions, nucleus-mitochondrion communication, and lipid droplet-mitochondrion interactions). The strategies that activate vagal system include direct vagal activation (electrical vagal stimulation and administration of vagal neurotransmitter acetylcholine) and pharmacological modulation (choline and cholinesterase inhibitors). The vagal system plays an important role in maintaining mitochondrial homeostasis and suppressing mitochondrial oxidative stress by promoting mitochondrial biogenesis and mitophagy, moderating mitochondrial fusion and fission, strengthening mitochondrial cristae stabilization, regulating mitochondrion-organelle interactions, and inhibiting mitochondrial Ca2+ overload. Therefore, enhancement of vagal activity can maintain mitochondrial homeostasis and represents a promising therapeutic strategy for cardiovascular diseases.

Mitoepigenetics: An intriguing regulatory layer in aging and metabolic-related diseases.

As a key organelle in eukaryotic cells, mitochondria play a central role in maintaining normal cellular functions. Mitochondrial dysfunction is reported to be closely related with aging and various diseases. Epigenetic modifications in nuclear genome provide a substantial layer for the modulation of nuclear-encoded gene expression. However, whether mitochondria could also be subjected to such similar epigenetic alterations and the involved mechanisms remain largely obscure and controversial. Recently, accumulating evidence has suggested that mitochondrial epigenetics, also known as mitoepigenetics may serve as an intriguing regulatory layer in mitochondrial DNA (mtDNA)-encoded gene expression. Given the potential regulatory role of mitoepigenetics, mitochondrial dysfunction derived from mitoepigenetics-induced abnormal gene expression could also be closely associated with aging and disease development. In this review, we summarized the recent advances in mitoepigenetics, with a special focus on mtDNA methylation in aging and metabolic-related diseases as well as the new methods and technologies for the study of mitoepigenetics. Uncovering the regulatory role of mitoepigenetics will help to understand the underlying mechanisms of mitochondrial dysfunction and provide novel strategies for delaying aging and preventing metabolic-related diseases.

Acetylcholine reduces palmitate-induced cardiomyocyte apoptosis by promoting lipid droplet lipolysis and perilipin 5-mediated lipid droplet-mitochondria interaction.

Lipid droplets (LDs), which are neutral lipid storage organelles, are important for lipid metabolism and energy homeostasis. LD lipolysis and interactions with mitochondria are tightly coupled to cellular metabolism and may be potential targets to buffer the effects of excessive toxic lipid species levels. Acetylcholine (ACh), the major neurotransmitter of the vagus nerve, exhibits cardioprotective effects. However, limited research has focused on its effects on LD lipolysis and the LD-mitochondria association in fatty acid (FA) overload models. Here, we reveal that palmitate (PA) induces an increase in expression of the FA transport protein cluster of differentiation 36 (CD36) and LD formation; remarkably reduces the expression of lipases involved in triacylglycerol (TAG) lipolysis, such as adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MGL); impairs LD-mitochondria interaction; and decreases perilipin 5 (PLIN5) expression, resulting in LD accumulation and mitochondrial dysfunction, which ultimately lead to cardiomyocyte apoptosis. ACh significantly upregulates PLIN5 expression and improved LD lipolysis and the LD-mitochondria association. Moreover, ACh reduces CD36 expression, LD deposition and mitochondrial dysfunction, ultimately suppressing apoptosis in PA-treated neonatal rat ventricular cardiomyocytes (NRVCs). Knockdown of PLIN5, which plays a role in LD-mitochondria contact site formation, abolishes the protective effects of ACh in PA-treated NRVCs. Thus, ACh protects cardiomyocytes from PA-induced apoptosis, at least partly, by promoting LD lipolysis and activating LD-mitochondria interactions via PLIN5. These findings may aid in developing novel therapeutic approaches that target LD lipolysis and PLIN5-mediated LD-mitochondria interactions to prevent or alleviate lipotoxic cardiomyopathy.

Hypermethylation of Hepatic Mitochondrial ND6 Provokes Systemic Insulin Resistance.

Mitochondrial epigenetics is rising as intriguing notion for its potential involvement in aging and diseases, while the details remain largely unexplored. Here it is shown that among the 13 mitochondrial DNA (mtDNA) encoded genes, NADH-dehydrogenase 6 (ND6) transcript is primarily decreased in obese and type 2 diabetes populations, which negatively correlates with its distinctive hypermethylation. Hepatic mtDNA sequencing in mice unveils that ND6 presents the highest methylation level, which dramatically increases under diabetic condition due to enhanced mitochondrial translocation of DNA methyltransferase 1 (DNMT1) promoted by free fatty acid through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Hepatic knockdown of ND6 or overexpression of Dnmt1 similarly impairs mitochondrial function and induces systemic insulin resistance both in vivo and in vitro. Genetic or chemical targeting hepatic DNMT1 shows significant benefits against insulin resistance associated metabolic disorders. These findings highlight the pivotal role of ND6 epigenetic network in regulating mitochondrial function and onset of insulin resistance, shedding light on potential preventive and therapeutic strategies of insulin resistance and related metabolic disorders from a perspective of mitochondrial epigenetics.

Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Vagal Activity, Gut Microbiota, and Branched-Chain Amino Acid Catabolism in Diabetic Mice.

The disruption of gut microbes is associated with diabetic cardiomyopathy, but the mechanism by which gut microbes affect cardiac damage remains unclear. We explored gut microbes and branched-chain amino acid (BCAA) metabolite catabolism in diabetic cardiomyopathy mice and investigated the cardioprotective effect of pyridostigmine. The experiments were conducted using a model of diabetic cardiomyopathy induced by a high-fat diet + streptozotocin in C57BL/6 mice. The results of high-throughput sequencing showed that diabetic cardiomyopathy mice exhibited decreased gut microbial diversity, altered abundance of the diabetes-related microbes, and increased abundance of the BCAA-producing microbes Clostridiales and Lachnospiraceae. In addition, diabetes downregulated tight junction proteins (ZO-1, occludin, and claudin-1) and increased intestinal permeability to impair the intestinal barrier. These impairments were accompanied by reduction in vagal activity that manifested as increased acetylcholinesterase levels, decreased acetylcholine levels, and heart rate variability, which eventually led to cardiac damage. Pyridostigmine enhanced vagal activity, restored gut microbiota homeostasis, decreased BCAA-producing microbe abundance, and improved the intestinal barrier to reduce circulating BCAA levels. Pyridostigmine also upregulated BCAT2 and PP2Cm and downregulated p-BCKDHA/BCKDHA and BCKDK to improve cardiac BCAA catabolism. Moreover, pyridostigmine alleviated abnormal mitochondrial structure; increased ATP production; decreased reactive oxygen species and mitochondria-related apoptosis; and attenuated cardiac dysfunction, hypertrophy, and fibrosis in diabetic cardiomyopathy mice. In conclusion, the gut microbiota, BCAA catabolism, and vagal activity were impaired in diabetic cardiomyopathy mice but were improved by pyridostigmine. These results provide novel insights for the development of a therapeutic strategy for diabetes-induced cardiac damage that targets gut microbes and BCAA catabolism.

Amelioration of circadian disruption and calcium-handling protein defects by choline alleviates cardiac remodeling in abdominal aorta coarctation rats.

The key pathophysiological process leading to heart failure is cardiac remodeling, a term referring to cardiac hypertrophy, fibrosis, and apoptosis. We explored circadian rhythm disruption and calcium dyshomeostasis in cardiac remodeling and investigated the cardioprotective effect of choline. The experiments were conducted using a model of cardiac remodeling by abdominal aorta coarctation (AAC) in Sprague-Dawley rats. In vitro cardiomyocyte remodeling was induced by exposing neonatal rat cardiomyocytes to angiotensin II. The circadian rhythms of the transcript levels of the seven major components of the mammalian clock (Bmal1, Clock, Rev-erbα, Per1/2, and Cry1/2) were altered in AAC rat hearts during a normal 24 h light/dark cycle. AAC also upregulated the levels of proteins that mediate store-operated Ca2+ entry/receptor-operated Ca2+ entry (stromal interaction molecule 1 [STIM1], Orai1, and transient receptor potential canonical 6 [TRPC6]) in rat hearts. Moreover, choline ameliorated circadian rhythm disruption, reduced the upregulated protein levels of STIM1, Orai1, and TRPC6, and alleviated cardiac dysfunction and remodeling (evidenced by attenuated cardiac hypertrophy, fibrosis, and apoptosis) in AAC rats. In vitro analyses showed that choline ameliorated calcium overload, downregulated STIM1, Orai1, and TRPC6, and inhibited thapsigargin-induced store-operated Ca2+ entry and 1-oleoyl-2-acetyl-sn-glycerol-induced receptor-operated Ca2+ entry in angiotensin II-treated cardiomyocytes. In conclusion, choline attenuated AAC-induced cardiac remodeling and cardiac dysfunction, which was related to amelioration of circadian rhythm disruption and attenuation of calcium-handling protein defects. Modulation of vagal activity by choline targeting the circadian rhythm and calcium homeostasis may have therapeutic potential for cardiac remodeling and heart failure.

Activation of M3AChR (Type 3 Muscarinic Acetylcholine Receptor) and Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) Signaling by Choline Alleviates Vascular Smooth Muscle Cell Phenotypic Switching and Vascular Remodeling.

OBJECTIVE: Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a critical role in atherosclerosis, vascular restenosis, and hypertension. Choline exerts cardioprotective effects; however, little is known about its effects on VSMC phenotypic switching and vascular remodeling. Here, we investigated whether choline modulates VSMC phenotypic changes and explored the underlying mechanisms. Approach and Results: In cultured VSMCs, choline promoted Nrf2 (nuclear factor erythroid 2-related factor 2) nuclear translocation, inducing the expression of HO-1 (heme oxygenase-1) and NQO-1 (NAD[P]H quinone oxidoreductase-1). Consequently, choline ameliorated Ang II (angiotensin II)-induced increases in NOX (NAD[P]H oxidase) expression and the mitochondrial reactive oxygen species level, thereby attenuating Ang II-induced VSMC phenotypic switching, proliferation, and migration, presumably via M3AChRs (type 3 muscarinic acetylcholine receptors). Downregulation of M3AChR or Nrf2 diminished choline-mediated upregulation of Nrf2, HO-1, and NQO-1 expression, as well as inhibition of VSMC phenotypic transformation, suggesting that M3AChR and Nrf2 activation are responsible for the protective effects of choline. Moreover, activation of the Nrf2 pathway by sulforaphane suppressed Ang II-induced VSMC phenotypic switching and proliferation, indicating that Nrf2 is a key regulator of VSMC phenotypic switching and vascular homeostasis. In a rat model of abdominal aortic constriction in vivo, choline attenuated VSMC phenotypic transformation and vascular remodeling in a manner related to activation of the Nrf2 pathway. CONCLUSIONS: These results reveal that choline impedes VSMC phenotypic switching, proliferation, migration, and vascular remodeling by activating M3AChR and Nrf2-antioxidant signaling and suggest a novel role for Nrf2 in VSMC phenotypic modulation.

Association of plasma cyclooxygenase-2 levels and genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults.

OBJECTIVE: Cyclooxygenase (COX)-2, an inducible isoform of the major rate-limiting enzymes that regulate the production of prostaglandins is associated with injury, inflammation and proliferation. We sought to examine whether plasma COX-2 levels and its genetic variants is associated with salt sensitivity, BP changes and/or hypertension in humans. METHODS: Eighty participants (aged 18-65 years) were maintained sequentially either on a usual diet for 3 days, a low-salt diet (3.0 g) for 7 days, and a high-salt diet (18.0 g) for an additional 7 days. In addition, we studied participants of the original Baoji Salt-Sensitive Study, recruited from 124 families from seven Chinese villages in 2004 who received the same salt intake intervention, and evaluated them for the development of hypertension. RESULTS: Plasma COX-2 levels were significantly decreased with reduction of salt intake from the usual to a low-salt diet and decreased further when converting from the low-salt to the high-salt diet. SNPs rs12042763 in the COX-2 gene was significantly associated with SBP responses to both low-salt and high-salt diet. SNPs rs689466 and rs12042763 were significantly associated with longitudinal changes in BPs. In addition, several COX-2 SNPs were significantly associated with incident hypertension over an 8-year follow-up. Gene-based analyses also supported the overall association of COX-2 with longitudinal changes in SBP and hypertension incidence. CONCLUSION: This study shows that dietary salt intake affects plasma COX-2 levels and that COX-2 may play a role in salt sensitivity, BP progression and development of hypertension in the Chinese populations studied.

Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice.

White adipose tissue (WAT) expansion in obesity occurs through enlargement of preexisting adipocytes (hypertrophy) and through formation of new adipocytes (adipogenesis). Adipogenesis results in WAT hyperplasia, smaller adipocytes and a metabolically more favourable form of obesity. How obesogenic WAT hyperplasia is induced remains, however, poorly understood. Here, we show that the mechanosensitive cationic channel Piezo1 mediates diet-induced adipogenesis. Mice lacking Piezo1 in mature adipocytes demonstrated defective differentiation of preadipocyte into mature adipocytes when fed a high fat diet (HFD) resulting in larger adipocytes, increased WAT inflammation and reduced insulin sensitivity. Opening of Piezo1 in mature adipocytes causes the release of the adipogenic fibroblast growth factor 1 (FGF1), which induces adipocyte precursor differentiation through activation of the FGF-receptor-1. These data identify a central feed-back mechanism by which mature adipocytes control adipogenesis during the development of obesity and suggest Piezo1-mediated adipocyte mechano-signalling as a mechanism to modulate obesity and its metabolic consequences.

Herba Houttuyniae Extract Benefits Hyperlipidemic Mice via Activation of the AMPK/PGC-1α/Nrf2 Cascade.

Hyperlipidemia is associated with metabolic disorders, but the detailed mechanisms and related interventions remain largely unclear. As a functional food in Asian diets, Herba houttuyniae has been reported to have beneficial effects on health. The present research was to investigate the protective effects of Herba houttuyniae aqueous extract (HAE) on hyperlipidemia-induced liver and heart impairments and its potential mechanisms. Male C57BL/6J mice were administered with 200 or 400 mg/kg/day HAE for 9 days, followed by intraperitoneal injection with 0.5 g/kg poloxamer 407 to induce acute hyperlipidemia. HAE treatment significantly attenuated excessive serum lipids and tissue damage markers, prevented hepatic lipid deposition, improved cardiac remodeling, and ameliorated hepatic and cardiac oxidative stress induced by hyperlipidemia. More importantly, NF-E2 related factor (Nrf2)-mediated antioxidant and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathways as well as mitochondrial complex activities were downregulated in the hyperlipidemic mouse livers and hearts, which may be attributable to the loss of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity: all of these changes were reversed by HAE supplementation. Our findings link the AMPK/PGC-1α/Nrf2 cascade to hyperlipidemia-induced liver and heart impairments and demonstrate the protective effect of HAE as an AMPK activator in the prevention of hyperlipidemia-related diseases.

Erratum to "Identification of atrial fibrillation-associated microRNAs in left and right atria of rheumatic mitral valve disease patients" [Genes Genet. Syst. (2019) 94, p. 23-34].

The article appeared in Genes & Genetic Systems Vol. 94, No. 1 (p. 23-34) was listed under the incorrect category. We apologize for this error. The correction is as follows:   Incorrect: Mini review   Identification of atrial fibrillation-associated microRNAs in left and right atria of rheumatic mitral valve disease patients Yang Yan, Rui Shi, Xiaojiang Yu, Chaofeng Sun, Weijin Zang and Hongyan Tian   Correct: Full paper   Identification of atrial fibrillation-associated microRNAs in left and right atria of rheumatic mitral valve disease patients Yang Yan, Rui Shi, Xiaojiang Yu, Chaofeng Sun, Weijin Zang and Hongyan Tian.

Regulation of mitochondrial cristae remodelling by acetylcholine alleviates palmitate-induced cardiomyocyte hypertrophy.

Mitochondrial dysfunction is associated with obesity-induced cardiac remodelling. Recent research suggests that the cristae are the true bioenergetic components of cells. Acetylcholine (ACh), the major neurotransmitter of the vagus nerve, exerts cardio-protective effects against ischaemia. This study investigated the role of cristae remodelling in palmitate (PA)-induced neonatal rat cardiomyocyte hypertrophy and explored the beneficial effects of ACh. We found loose, fragmented and even lysed cristae in PA-treated neonatal cardiomyocytes along with declines in mitochondrial network and complex expression and overproduction of mitochondrial reactive oxygen species (ROS); these changes ultimately resulted in increased myocardial size. Overexpression of mitofilin by adenoviral infection partly improved cristae shape, mitochondrial network, and ATP content and attenuated cell hypertrophy. Interestingly, siRNA-mediated AMP-activated protein kinase (AMPK) silencing increased the number of cristae with a balloon-like morphology without disturbing mitofilin expression. Furthermore, AMPK knockdown abolished the effects of mitofilin overexpression on cristae remodelling and inhibited the interaction of mitofilin with sorting and assembly machinery 50 (Sam50) and coiled-coil helix coiled-coil helix domain-containing protein 3 (CHCHD3), two core components of the mitochondrial contact site and cristae organizing system (MICOS) complex. Intriguingly, ACh upregulated mitofilin expression and AMPK phosphorylation via the muscarinic ACh receptor (MAChR). Moreover, ACh enhanced protein-protein interactions between mitofilin and other components of the MICOS complex, thereby preventing PA-induced mitochondrial dysfunction and cardiomyocyte hypertrophy; however, these effects were abolished by AMPK silencing. Taken together, our data suggest that ACh improves cristae remodelling to defend against PA-induced myocardial hypertrophy, presumably by increasing mitofilin expression and activating AMPK to form the MICOS complex through MAChR. These results suggest new and promising therapeutic approaches targeting mitochondria to prevent lipotoxic cardiomyopathy.

Pyridostigmine regulates glucose metabolism and mitochondrial homeostasis to reduce myocardial vulnerability to injury in diabetic mice.

Diabetic patients are more susceptible to myocardial ischemia damage than nondiabetic patients, with worse clinical outcomes and greater mortality. The mechanism may be related to glucose metabolism, mitochondrial homeostasis, and oxidative stress. Pyridostigmine may improve vagal activity to protect cardiac function in cardiovascular diseases. Researchers have not determined whether pyridostigmine regulates glucose metabolism and mitochondrial homeostasis to reduce myocardial vulnerability to injury in diabetic mice. In the present study, autonomic imbalance, myocardial damage, mitochondrial dysfunction, and oxidative stress were exacerbated in isoproterenol-stimulated diabetic mice, revealing the myocardial vulnerability of diabetic mice to injury compared with mice with diabetes or exposed to isoproterenol alone. Compared with normal mice, the expression of glucose transporters (GLUT)1/4 phosphofructokinase (PFK) FB3, and pyruvate kinase isoform (PKM) was decreased in diabetic mice, but increased in isoproterenol-stimulated normal mice. Following exposure to isoproterenol, the expression of (GLUT)1/4 phosphofructokinase (PFK) FB3, and PKM decreased in diabetic mice compared with normal mice. The downregulation of SIRT3/AMPK and IRS-1/Akt in isoproterenol-stimulated diabetic mice was exacerbated compared with that in diabetic mice or isoproterenol-stimulated normal mice. Pyridostigmine improved vagus activity, increased GLUT1/4, PFKFB3, and PKM expression, and ameliorated mitochondrial dysfunction and oxidative stress to reduce myocardial damage in isoproterenol-stimulated diabetic mice. Based on these results, it was found that pyridostigmine may reduce myocardial vulnerability to injury via the SIRT3/AMPK and IRS-1/Akt pathways in diabetic mice with isoproterenol-induced myocardial damage. This study may provide a potential therapeutic target for myocardial damage in diabetic patients.

[Recent progress on obesity-induced myocardial remodeling and its possible mechanism of mitochondrial dyshomeostasis].

Obesity is an important risk factor for cardiovascular diseases, which can lead to a variety of cardiovascular diseases including myocardial remodeling. Obesity may induce myocardial dysfunction by affecting hemodynamics, inducing autonomic imbalance, adipose tissue dysfunction, and mitochondrial dyshomeostasis. The key necessary biochemical functions for metabolic homeostasis are performed in mitochondria, and mitochondrial homeostasis is considered as one of the key determinants for cell viability. Mitochondrial homeostasis is regulated by dynamic regulation of mitochondrial fission and fusion, as well as mitochondrial cristae remodeling, biogenesis, autophagy, and oxidative stress. The mitochondrial fission-fusion and morphological changes of mitochondrial cristae maintain the integrity of the mitochondrial structure. The mitochondria maintain a "healthy" state by balancing biogenesis and autophagy, while reactive oxygen species can act as signaling molecules to regulate intracellular signaling. The excessive accumulation of lipids and lipid metabolism disorder in obesity leads to mitochondrial dyshomeostasis, which activate the apoptotic cascade and lead to myocardial remodeling. In this review, we provide an overview of the recent research progress on obesity-induced myocardial remodeling and its possible mechanism of mitochondrial dyshomeostasis.

Punicalagin attenuates endothelial dysfunction by activating FoxO1, a pivotal regulating switch of mitochondrial biogenesis.

Accumulating evidence has elucidated that hyperlipidemia is closely associated with an increasing prevalence of CVDs (cardiovascular diseases) because of endothelial dysfunction. In the present study, we investigated the effect and mechanism of PU (Punicalagin), a major ellagitannin in pomegranate, on endothelial dysfunction both in vivo and in vitro. In vivo, PU significantly ameliorated hyperlipidemia-induced accumulation of serum triglyceride and cholesterol as well as endothelial and mitochondrial dysfunction of thoracic aorta. Intriguingly, the FoxO1 (forkhead box O1) pathway was activated, which may account for prevention of vascular dysfunction and mitochondrial loss via upregulating mitochondrial biogenesis. In line, through in vitro cell cultures, our study demonstrated that PU not only increased the total FoxO1 protein, but also enhanced its nuclear translocation. In addition, silencing of FoxO1 remarkably abolished the ability of PU to augment the mitochondrial biogenesis, eNOS (endothelial NO synthase) expression, and oxidative stress, implying the irreplaceable role of FoxO1 in regulating endothelial function in the presence of PU. Conversely, suppression of excessive ROS (reactive oxygen species) secured the PA (palmitate)-induced decrease of FoxO1 expression, implying that there was a cross-talk between FoxO1 pathway and ROS. Concomitantly, the inflammatory response in current study was primarily mediated via p38 MAPK/NF-κB signaling pathway besides of FoxO1 pathway. Taken together, our findings suggest that PU ameliorates endothelial dysfunction by activating FoxO1 pathway, a pivotal regulating switch of mitochondrial biogenesis.