Omega-3 Lipid Mediators: Modulation of the M1/M2 Macrophage Phenotype and Its Protective Role in Chronic Liver Diseases.

The complex interplay between dietary factors, inflammation, and macrophage polarization is pivotal in the pathogenesis and progression of chronic liver diseases (CLDs). Omega-3 fatty acids (FAs) have brought in attention due to their potential to modulate inflammation and exert protective effects in various pathological conditions. Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise in mitigating inflammation and enhancing the resolution of inflammatory responses. They influence the M1/M2 macrophage phenotype balance, promoting a shift towards the M2 anti-inflammatory phenotype. Specialized pro-resolving mediators (SPMs), such as resolvins (Rvs), protectins (PDs), and maresins (MaRs), have emerged as potent regulators of inflammation and macrophage polarization. They show anti-inflammatory and pro-resolving properties, by modulating the expression of cytokines, facilitate the phagocytosis of apoptotic cells, and promote tissue repair. MaR1, in particular, has demonstrated significant hepatoprotective effects by promoting M2 macrophage polarization, reducing oxidative stress, and inhibiting key inflammatory pathways such as NF-κB. In the context of CLDs, such as nonalcoholic fatty liver disease (NAFLD) and cirrhosis, omega-3s and their SPMs have shown promise in attenuating liver injury, promoting tissue regeneration, and modulating macrophage phenotypes. The aim of this article was to analyze the emerging role of omega-3 FAs and their SPMs in the context of macrophage polarization, with special interest in the mechanisms underlying their effects and their interactions with other cell types within the liver microenvironment, focused on CLDs and the development of novel therapeutic strategies.

Exercise Induces an Augmented Skeletal Muscle Mitochondrial Unfolded Protein Response in a Mouse Model of Obesity Produced by a High-Fat Diet.

Increase in body fat contributes to loss of function and changes in skeletal muscle, accelerating sarcopenia, a phenomenon known as sarco-obesity or sarcopenic obesity. Studies suggest that obesity decreases the skeletal muscle (SM)'s ability to oxidize glucose, increases fatty acid oxidation and reactive oxygen species production, due to mitochondrial dysfunction. Exercise improves mitochondrial dysfunction in obesity; however, it is not known if exercise regulates the mitochondrial unfolded protein response (UPRmt) in the SM. Our study aimed to determine the mito-nuclear UPRmt in response to exercise in a model of obesity, and how this response is associated with the improvement in SM functioning after exercise training. C57BL/6 mice were fed a normal diet and high-fat diet (HFD) for 12 weeks. After 8 weeks, animals were subdivided into sedentary and exercised for the remaining 4 weeks. Grip strength and maximal velocity of mice submitted to HFD improved after training. Our results show an increase in the activation of UPRmt after exercise while in obese mice, proteostasis is basally decreased but shows a more pronounced increase with exercise. These results correlate with improvement in the circulating triglycerides, suggesting mitochondrial proteostasis could be protective and could be related to mitochondrial fuel utilization in SM.

Glucocorticoid Receptor ß Overexpression Has Agonist-Independent Insulin-Mimetic Effects on HepG2 Glucose Metabolism.

Glucocorticoids (GC) are steroids hormones that drive circulating glucose availability through gluconeogenesis in the liver. However, alternative splicing of the GR mRNA produces two isoforms, termed GRα and GRß. GRα is the classic receptor that binds to GCs and mediates the most described actions of GCs. GRß does not bind GCs and acts as a dominant-negative inhibitor of GRα. Moreover, GRß has intrinsic and GRα-independent transcriptional activity. To date, it remains unknown if GRß modulates glucose handling in hepatocytes. Therefore, the study aims to characterize the impact of GRß overexpression on glucose uptake and storage using an in vitro hepatocyte model. Here we show that GRß overexpression inhibits the induction of gluconeogenic genes by dexamethasone. Moreover, GRß activates the Akt pathway, increases glucose transports mRNA, increasing glucose uptake and glycogen storage as an insulin-mimetic. Our results suggest that GRß has agonist-independent insulin-mimetic actions in HepG2 cells.

Anthocyanins from Aristotelia chilensis Prevent Olanzapine-Induced Hepatic-Lipid Accumulation but Not Insulin Resistance in Skeletal Muscle Cells.

Type 2 diabetes and obesity are major problems worldwide and dietary polyphenols have shown efficacy to ameliorate signs of these diseases. Anthocyanins from berries display potent antioxidants and protect against weight gain and insulin resistance in different models of diet-induced metabolic syndrome. Olanzapine is known to induce an accelerated form of metabolic syndrome. Due to the aforementioned, we evaluated whether delphinidin-3,5-O-diglucoside (DG) and delphinidin-3-O-sambubioside-5-O-glucoside (DS), two potent antidiabetic anthocyanins isolated from Aristotelia chilensis fruit, could prevent olanzapine-induced steatosis and insulin resistance in liver and skeletal muscle cells, respectively. HepG2 liver cells and L6 skeletal muscle cells were co-incubated with DG 50 µg/mL or DS 50 µg/mL plus olanzapine 50 µg/mL. Lipid accumulation was determined in HepG2 cells while the expression of p-Akt as a key regulator of the insulin-activated signaling pathways, mitochondrial function, and glucose uptake was assessed in L6 cells. DS and DG prevented olanzapine-induced lipid accumulation in liver cells. However, insulin signaling impairment induced by olanzapine in L6 cells was not rescued by DS and DG. Thus, anthocyanins modulate lipid metabolism, which is a relevant factor in hepatic tissue, but do not significantly influence skeletal muscle, where a potent antioxidant effect of olanzapine was found.

Impact of Mitophagy and Mitochondrial Unfolded Protein Response as New Adaptive Mechanisms Underlying Old Pathologies: Sarcopenia and Non-Alcoholic Fatty Liver Disease.

Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPRmt) to promote cell recovery and survival of the mitochondrial network; (ii) the mitophagy process to eliminate altered or dysfunctional mitochondria. For these purposes, the former response induces the expression of chaperones, proteases, antioxidant components and protein import and assembly factors, whereas the latter is signaled through the activation of the PINK1/Parkin and BNIP3/NIX pathways. These adaptive mechanisms may be compromised during aging, leading to the development of several pathologies including sarcopenia, defined as the loss of skeletal muscle mass and performance; and non-alcoholic fatty liver disease (NAFLD). These age-associated diseases are characterized by the progressive loss of organ function due to the accumulation of reactive oxygen species (ROS)-induced damage to biomolecules, since the ability to counteract the continuous and large generation of ROS becomes increasingly inefficient with aging, resulting in mitochondrial dysfunction as a central pathogenic mechanism. Nevertheless, the role of the integrated stress response (ISR) involving UPRmt and mitophagy in the development and progression of these illnesses is still a matter of debate, considering that some studies indicate that the prolonged exposure to low levels of stress may trigger these mechanisms to maintain mitohormesis, whereas others sustain that chronic activation of them could lead to cell death. In this review, we discuss the available research that contributes to unveil the role of the mitochondrial UPR in the development of sarcopenia, in an attempt to describe changes prior to the manifestation of severe symptoms; and in NAFLD, in order to prevent or reverse fat accumulation and its progression by means of suitable protocols to be addressed in future studies.

Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain.

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

Metformin-Associated Lactic Acidosis Undergoing Renal Replacement Therapy in Intensive Care Units: A Five-Million Population-Based Study in the North-West of Italy.

BACKGROUND: Metformin-associated lactic acidosis (MALA) is a severe complication of drug administration with significant morbidity and mortality. So far no study in large population areas have examined the incidence, clinical profile and outcome of acute kidney injury (AKI)-MALA patients admitted in intensive care units (ICUs) and treated by renal replacement therapy (MALA-RRT). METHODS: Retrospective analysis over a 6-year period (2010-2015) in Piedmont and Aosta Valley regions (5,305,940 inhabitants, 141,174 diabetics treated with metformin) of all MALA-RRT cases. RESULTS: One hundred and seventeen cases of AKI-MALA-RRT were observed (12.04/100,000 metformin treated diabetics, 1.45% of all RRT-ICU patients). Survival rate was 78.3%. The average duration of RRT was 4.0 days at mean dialysis effluent of 977 mL/kg/day. At admission most patients were dehydrated, and experienced shock and oliguria. CONCLUSION: Our data showed that MALA-RRT is a common complication, needing more prevention. Adopted policy of early, extended, continuous and high efficiency dialysis could contribute to an observed high survival rate. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=471917.

Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway.

Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, and their morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy is still poorly understood. Here, we show that treatment of cultured neonatal rat cardiomyocytes with the hypertrophic agonist norepinephrine promotes mitochondrial fission (characterized by a decrease in mitochondrial mean volume and an increase in the relative number of mitochondria per cell) and a decrease in mitochondrial function. We demonstrate that norepinephrine acts through α1-adrenergic receptors to increase cytoplasmic Ca(2+), activating calcineurin and promoting migration of the fission protein Drp1 (encoded by Dnml1) to mitochondria. Dominant-negative Drp1 (K38A) not only prevented mitochondrial fission, it also blocked hypertrophic growth of cardiomyocytes in response to norepinephrine. Remarkably, an antisense adenovirus against the fusion protein Mfn2 (AsMfn2) was sufficient to increase mitochondrial fission and stimulate a hypertrophic response without agonist treatment. Collectively, these results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodeling.

Atrial Function Assessed by Speckle Tracking Echocardiography Is a Good Predictor of Postoperative Atrial Fibrillation in Elderly Patients.

OBJECTIVE: Advanced age is an independent predictor of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass surgery. We evaluated whether left atrial (LA) dysfunction assessed by strain contributes to identifying elderly patients prone to POAF. METHODS: Case-control study of 70 subjects undergoing coronary artery bypass surgery. Clinical and laboratory characteristics were recorded at baseline and 72 hours after surgery. Echocardiography was performed during the preoperative period; LA dimensions and deformation by strain (systolic wave [LASs]) as well as strain rate (systolic wave [LASRs] and atrial contraction wave [LASRa]) were assessed. RESULTS: Postoperative atrial fibrillation occurred in 38.5% of patients within the first 72 hours after surgery (28.5% of the younger vs. 48.6% of the older group). Baseline and postoperative inflammatory markers as well as total surgical and aortic clamp time were similar between groups. LA function was markedly impaired in subjects with POAF. Age correlated with LASs, LASRs, and LASRa. These associations remained consistent when subjects 75 years or older were considered separately. Both LASs and LASRa for patients with or without POAF, respectively, were significantly impaired in elderly subjects with POAF. Multivariate analysis provided further evidence that both LASs and age are independent predictors for POAF. CONCLUSION: Age-related changes in atrial function preceding atrial dilation are evident only upon LA strain analysis. LA strain impairment is an independent predictor of POAF irrespective of age and may serve as a surrogate marker for biological processes involved in establishing the substrate for POAF.

Mitochondrial fragmentation impairs insulin-dependent glucose uptake by modulating Akt activity through mitochondrial Ca2+ uptake.

Insulin is a major regulator of glucose metabolism, stimulating its mitochondrial oxidation in skeletal muscle cells. Mitochondria are dynamic organelles that can undergo structural remodeling in order to cope with these ever-changing metabolic demands. However, the process by which mitochondrial morphology impacts insulin signaling in the skeletal muscle cells remains uncertain. To address this question, we silenced the mitochondrial fusion proteins Mfn2 and Opa1 and assessed insulin-dependent responses in L6 rat skeletal muscle cells. We found that mitochondrial fragmentation attenuates insulin-stimulated Akt phosphorylation, glucose uptake and cell respiratory rate. Importantly, we found that insulin induces a transient rise in mitochondrial Ca(2+) uptake, which was attenuated by silencing Opa1 or Mfn2. Moreover, treatment with Ruthenium red, an inhibitor of mitochondrial Ca(2+) uptake, impairs Akt signaling without affecting mitochondrial dynamics. All together, these results suggest that control of mitochondrial Ca(2+) uptake by mitochondrial morphology is a key event for insulin-induced glucose uptake.

Relevant Aspects of Combined Protocols for Prevention of N(M)AFLD and Other Non-Communicable Diseases.

Obesity is a global health issue characterized by the excessive fat accumulation, leading to an increased risk of chronic noncommunicable diseases (NCDs), including metabolic dysfunction-associated fatty liver disease (MAFLD), which can progress from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, there are no approved pharmacological protocols for prevention/treatment of MAFLD, and due the complexity lying beneath these mechanisms, monotherapies are unlikely to be efficacious. This review article analyzes the possibility that NCDs can be prevented or attenuated by the combination of bioactive substances, as they could promote higher response rates, maximum reaction results, additive or synergistic effects due to compounds having similar or different mechanisms of action and/or refraining possible side effects, related to the use of lower doses and exposures times than monotherapies. Accordingly, prevention of mouse MAFLD is observed with the combination of the omega-3 docosahexaenoic acid with the antioxidant hydroxytyrosol, whereas attenuation of mild cognitive impairment is attained by folic acid plus cobalamin in elderly patients. The existence of several drawbacks underlying published monotherapies or combined trials, opens space for adequate and stricter experimental and clinical tryouts to achieve meaningful outcomes with human applicability.

Cellular Functional, Protective or Damaging Responses Associated with Different Redox Imbalance Intensities: A Comprehensive Review.

Reactive species (RS) are produced in aerobic and anaerobic cells at different concentrations and exposure times, which may trigger diverse responses depending on the cellular antioxidant potential and defensive devices. Study searches were carried out using the PubMed database of the National Library of Medicine-National Institutes of Health. Cellular RS include reactive oxygen (ROS), nitrogen (RNS), lipid (RLS) and electrophilic species that determine either cell homeostasis or dysfunctional biomolecules. The complexity of redox signalling is associated with the variety of RS produced, the reactivity of the target biomolecules with RS, the multiplicity of the counteracting processes available, and the exposure time. The continuous distortion in the prooxidant/ antioxidant balance favoring the former is defined as oxidative stress, whose intensity determines (i) the basal not harmful unbalance (oxidative eustress) at RS levels in the pM to nM range that supports physiological processes (e.g., immune function, thyroid function, insulin action) and beneficial responses to external interventions via redox signalling; or (ii) the excessive, toxic distortion (oxidative distress) at RS levels exceeding those in the oxidative eustress zone, leading to the unspecific oxidation of biomolecules and loss of their functions causing cell death with associated pathological states. The cellular redox imbalance is a complex phenomenon whose underlying mechanisms are beginning to be understood, although how RS initiates cell signalling is a matter of debate. Knowledge of this aspect will provide a better understanding of how RS triggers the pathogenesis and progression of the disease and uncover future therapeutic measures.

Changes in macrophage immunometabolism as a marker of skeletal muscle dysfunction across the lifespan.

One of the most pronounced changes in the elderly is loss of strength and mobility due to the decline of skeletal muscle function, resulting in a multifactorial condition termed sarcopenia. Although significant clinical changes begin to manifest at advanced ages, recent studies have shown that changes at the cellular and molecular level precede the symptomatology of sarcopenia. By utilizing a single-cell transcriptomic atlas of mouse skeletal muscle across the lifespan, we identified a clear sign of immune senescence that presents during middle age. More importantly, the change in macrophage phenotype in middle age may explain the changes in extracellular matrix composition, especially collagen synthesis, that contributes to fibrosis and overall muscle weakness with advanced age. Our results show a novel paradigm whereby skeletal muscle dysfunction is driven by alterations in tissue-resident macrophages before the appearance of clinical symptoms in middle-aged mice, providing a new therapeutic approach via regulation of immunometabolism.

Increase of continuous treatments and regional citrate anticoagulation during renal replacement therapy in the ICUs of the North-West of Italy from 2007 to 2015.

BACKGROUND: Few reports have addressed the change in renal replacement therapy (RRT) management in the Intensive care Units (ICUs) over the years in western countries. This study aims to assess the trend of dialytic practice in a 4.5-million population-based study of the northwest of Italy. METHODS: A nine-year survey covering all the RRT provided in the ICUs. Consultant nephrologists of the 26 Nephrology and Dialysis centers reported their activities in the years 2007, 2009, 2012, and 2015. RESULTS: From 2007 to 2015 the patients treated increased from 1042 to 1139, and the incidence of RRT from 254 to 263 cases/10^6 inhabitants. The workload for dialysis center was higher in the larger hub hospitals. RRT for acute kidney injury (AKI), continuation of treatment in chronically dialyzed patients, or extrarenal indications accounted for about the stable rate of 70, 25 and 5% of all RRT sessions, respectively. Continuous modality days increased from 2731 days (39.5%) in 2007 to 5076 (70.6%) in 2015, when the continuous+prolonged treatment days were 6880/7196 (95.6% of total days). As to RRT timing, in 2015 only the classical clinical criteria, and no K-DIGO stage were adopted by most Centers. As to RRT interruption, in 2015 urine volume was the first criterion. Implementation of citrate anticoagulation (RCA) for RRT patients significantly increased from 2.8% in 2007 to 30.9% in 2015, when it was applied in all 26 Centers. CONCLUSIONS: From 2007 to 2015, current practice has changed towards shared protocols, with increasing continuous modality and RCA implementation.

Urinary secretion and extracellular aggregation of mutant uromodulin isoforms.

Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein.

Mitochondria, myocardial remodeling, and cardiovascular disease.

The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease.

[Renal biopsy practice in Piedmont and Valle d'Aosta]. / Indagine sulle modalità di esecuzione delle biopsia renale in Piemonte e Valle d'Aosta.

In 2010 a questionnaire was administered to the renal units of Piedmont and Valle d'Aosta to analyze their procedures for renal biopsy (RB). Seventy-eight percent of units performed RBs, 57% for more than 20 years, but only 43% performed at least 20 BRs per year. 20/21 units performed RB in an inpatient setting and 1/21 in day hospital with the patient remaining under observation the night after. Thirty-two percent did not consider a single kidney as a contraindication to RB, 59% considered it a relative contraindication and 9% considered it an absolute contraindication. In 90.5% of units there was a specific protocol for patient preparation for RB and 86% used a specific informed consent form. Ninety-five percent of units performed ultrasound-guided RB, 60% of them using needle guides attached to the probe. In 81% of units the left side was preferred; 71% put a pillow under the patient's abdomen. All units used disposable, automated or semi-automated needles. Needle size was 16G in 29%, 18G in 58%, and both 16G and 18G in 14% of units; 1 to 3 samples were drawn. One third of units had a microscope available for immediate evaluation of specimen adequacy. After RB, 86% of units kept patients in the prone position for 2-6 hours and all prescribed a period of bed rest (at least 24 hours in 90.5%). 90.5% of units followed a specific postbiopsy observation protocol consisting of blood pressure, heart rate and red blood cell measurements at different times, and urine monitoring and ultrasound control within 12-24 hours (only half of them also employing color Doppler). One third of all units discharged patients after 1 day and two thirds after 2-3 days; all prescribed abstention from effort and from antiplatelet drugs for 7-15 days. In 9 units both RB and tissue processing and examination were done in the same hospital, while 12 units sent the samples elsewhere. 76% obtained results in 2-4 days, 19% in 6-7 days, and 5% in 10-15 days. Less than 20% of the interviewed operators were fully familiar with the clauses of hospital insurance securing their activity. Use of RB is widespread in Piedmont and Valle d'Aosta but its practice shows variation between centers.

Standpoints in mitochondrial dysfunction: Underlying mechanisms in search of therapeutic strategies.

Mitochondrial dysfunction has been defined as a reduced efficiency of mitochondria to produce ATP given by a loss of mitochondrial membrane potential, alterations in the electron transport chain (ETC) function, with increase in reactive oxygen species (ROS) generation and decrease in oxygen consumption. During the last decades, mitochondrial dysfunction has been the focus of many researchers as a convergent point for the pathophysiology of several diseases. Numerous investigations have demonstrated that mitochondrial dysfunction is detrimental to cells, tissues and organisms, nevertheless, dysfunctional mitochondria can signal in a particular way in response to stress, a characteristic that may be useful to search for new therapeutic strategies with a common feature. The aim of this review addresses mitochondrial dysfunction and stress signaling as a promising target for future drug development.

Cardioprotective Antioxidant and Anti-Inflammatory Mechanisms Induced by Intermittent Hypobaric Hypoxia.

More than 80 million people live and work (in a chronic or intermittent form) above 2500 masl, and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 100,000 people work in high-altitude shifts, where stays in the lowlands are interspersed with working visits in the highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders due to increased free radical formation and decreased antioxidant capacity. However, intermittent hypoxia (IH) induces preconditioning in animal models, generating cardioprotection. Here, we aim to describe the responses of a cardiac function to four cycles of intermittent hypobaric hypoxia (IHH) in a rat model. The twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days of hypoxia + 4 days of normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the fourth cycle, cardiac structural and functional variables were also determined by echocardiography; furthermore, cardiac oxidative stress biomarkers (4-Hydroxynonenal, HNE; nitrotyrosine, NT), antioxidant enzymes, and NLRP3 inflammasome panel expression are also determined. Our results show a higher ejection and a shortening fraction of the left ventricle function by the end of the fourth cycle. Furthermore, cardiac tissue presented a decreased expression of antioxidant proteins. However, a decrease in IL-1ß, TNF-αn, and oxidative stress markers is observed in IHH compared to normobaric hypoxic controls. Non-significant differences were found in protein levels of NLRP3 and caspase-1. IHH exposure determines structural and functional heart changes. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.