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Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.

ABSTRACT: Diastolic heart failure (HF) i.e., "HF with preserved ejection fraction" (HF-preserved EF) accounts for up to 50% of all HF presentations; however there have been no therapeutic advances. This stems in part from an incomplete understanding about HF-preserved EF. Hypertension is the major cause of HF-preserved EF whilst HF-preserved EF is also highly associated with obesity. Similarly, excessive reactive oxygen species (ROS), i.e., oxidative stress occurs in hypertension and obesity, sensitizing the heart to the renin-angiotensin-aldosterone system, inducing autophagic type-II programmed cell death and accelerating the propensity to adverse cardiac remodeling, diastolic dysfunction and HF. Adiponectin (APN), an adipokine, mediates cardioprotective actions but it is unknown if APN modulates cardiomyocyte autophagy. We tested the hypothesis that APN ameliorates oxidative stress-induced autophagy in cardiomyocytes. Isolated adult rat ventricular myocytes were pretreated with recombinant APN (30 µg/mL) followed by 1mM hydrogen peroxide (H2O2) exposure. Wild type (WT) and APN-deficient (APN-KO) mice were infused with angiotensin (Ang)-II (3.2 mg/kg/d) for 14 days to induced oxidative stress. Autophagy-related proteins, mTOR, AMPK and ERK expression were measured. H2O2 induced LC3I to LC3II conversion by a factor of 3.4±1.0 which was abrogated by pre-treatment with APN by 44.5±10%. However, neither H2O2 nor APN affected ATG5, ATG7, or Beclin-1 expression. H2O2 increased phospho-AMPK by 49±6.0%, whilst pretreatment with APN decreased phospho-AMPK by 26±4%. H2O2 decreased phospho-mTOR by 36±13%, which was restored by APN. ERK inhibition demonstrated that the ERK-mTOR pathway is involved in H2O2-induced autophagy. Chronic Ang-II infusion significantly increased myocardial LC3II/I protein expression ratio in APN-KO vs. WT mice. These data suggest that excessive ROS caused cardiomyocyte autophagy which was ameliorated by APN by inhibiting an H2O2-induced AMPK/mTOR/ERK-dependent mechanism. These findings demonstrate the anti-oxidant potential of APN in oxidative stress-associated cardiovascular diseases, such as hypertension-induced HF-preserved EF.

SUBMITTER: Essick EE

PROVIDER: S-EPMC3716763 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.

Essick Eric E EE Wilson Richard M RM Pimentel David R DR Shimano Masayuki M Baid Simoni S Ouchi Noriyuki N Sam Flora F

PloS one 20130719 7

Diastolic heart failure (HF) i.e., "HF with preserved ejection fraction" (HF-preserved EF) accounts for up to 50% of all HF presentations; however there have been no therapeutic advances. This stems in part from an incomplete understanding about HF-preserved EF. Hypertension is the major cause of HF-preserved EF whilst HF-preserved EF is also highly associated with obesity. Similarly, excessive reactive oxygen species (ROS), i.e., oxidative stress occurs in hypertension and obesity, sensitizing ...[more]

PMID: 23894332

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Project description:Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. Mitochondria-induced oxidative stress has been shown to play a major role in a wide range of pathologies in several organs, including the heart. Few studies have investigated whether enhanced autophagy can offer protection against mitochondrially-generated oxidative stress. We induced mitochondrial stress in cardiomyocytes using antimycin A (AMA), which increased mitochondrial superoxide generation, decreased mitochondrial membrane potential and depressed cellular respiration. In addition, AMA augmented nuclear DNA oxidation and cell death in cardiomyocytes. Interestingly, although oxidative stress has been proposed to induce autophagy, treatment with AMA did not result in stimulation of autophagy or mitophagy in cardiomyocytes. Our results showed that the MTOR inhibitor rapamycin induced autophagy, promoted mitochondrial clearance and protected cardiomyocytes from the cytotoxic effects of AMA, as assessed by apoptotic marker activation and viability assays in both mouse atrial HL-1 cardiomyocytes and human ventricular AC16 cells. Importantly, rapamycin improved mitochondrial function, as determined by cellular respiration, mitochondrial membrane potential and morphology analysis. Furthermore, autophagy induction by rapamycin suppressed the accumulation of ubiquitinylated proteins induced by AMA. Inhibition of rapamycin-induced autophagy by pharmacological or genetic interventions attenuated the cytoprotective effects of rapamycin against AMA. We propose that rapamycin offers cytoprotection against oxidative stress by a combined approach of removing dysfunctional mitochondria as well as by degrading damaged, ubiquitinated proteins. We conclude that autophagy induction by rapamycin could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes.

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Project description:Testes produce sperms, and gamete generation relies on a proper niche environment. The disruption of hierarchical regulatory homeostasis in Leydig or Sertoli cells may evoke a sterile phenotype in humans. In this study, we recapitulated type 2 diabetes mellitus by using a high-fat diet- (HFD-) fed mouse model to identify the phenotype and potential mechanism of diabetes-induced testicular impairment. At the end of the study, blood glucose levels, testosterone structure, testicular antioxidant capacity, and testosterone level and the expression of hypoxia-inducible factor- (HIF-) 1α, apoptosis-related protein cleaved-caspase3, and autophagy-related proteins such as LC3I/II, p62, and Beclin1 were evaluated. We found that long-term HFD treatment causes the development of diabetes mellitus, implicating increased serum glucose level, cell apoptosis, and testicular atrophy (P < 0.05 vs. Ctrl). Mechanistically, the results showed enhanced expression of HIF-1α in both Sertoli and Leydig cells (P < 0.05 vs. Ctrl). Advanced glycation end products (AGEs) were demonstrated to be a potential factor leading to HIF-1α upregulation in both cell types. In Sertoli cells, high glucose treatment had minor effects on Sertoli cell autophagy. However, AGE treatment stagnated the autophagy flux and escalated cell apoptosis (P < 0.05 vs. Ctrl+Ctrl). In Leydig cells, high glucose treatment was adequate to encumber autophagy induction and enhance oxidative stress. Similarly, AGE treatment facilitated HIF-1α expression and hampered testosterone production (P < 0.05 vs. Ctrl+Ctrl). Overall, these findings highlight the dual effects of diabetes on autophagy regulation in Sertoli and Leydig cells while imposing oxidative stress in both cell types. Furthermore, the upregulation of HIF-1α, which could be triggered by AGE treatment, may negatively affect both cell types. Together, these findings will help us further understand the molecular mechanism of diabetes-induced autophagy dysregulation and testicular impairment, enriching the content of male reproductive biology in diabetic patients.

Dataset Information

Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.

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Adiponectin modulates oxidative stress-induced autophagy in cardiomyocytes.

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