Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice.

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.

Moderate-Intensity and High-Intensity Interval Exercise Training Offer Equal Cardioprotection, with Different Mechanisms, during the Development of Type 2 Diabetes in Rats.

Endurance exercise training is a promising cardioprotective strategy in type 2 diabetes mellitus (T2DM), but the impact of its intensity is not clear. We aimed to investigate whether and how isocaloric moderate-intensity exercise training (MIT) and high-intensity interval exercise training (HIIT) could prevent the adverse cardiac remodeling and dysfunction that develop T2DM in rats. Male rats received a Western diet (WD) to induce T2DM and underwent a sedentary lifestyle (n = 7), MIT (n = 7) or HIIT (n = 8). Insulin resistance was defined as the HOMA-IR value. Cardiac function was assessed with left ventricular (LV) echocardiography and invasive hemodynamics. A qPCR and histology of LV tissue unraveled underlying mechanisms. We found that MIT and HIIT halted T2DM development compared to in sedentary WD rats (p < 0.05). Both interventions prevented increases in LV end-systolic pressure, wall thickness and interstitial collagen content (p < 0.05). In LV tissue, HIIT tended to upregulate the gene expression of an ROS-generating enzyme (NOX4), while both modalities increased proinflammatory macrophage markers and cytokines (CD86, TNF-α, IL-1ß; p < 0.05). HIIT promoted antioxidant and dicarbonyl defense systems (SOD2, glyoxalase 1; p < 0.05) whereas MIT elevated anti-inflammatory macrophage marker expression (CD206, CD163; p < 0.01). We conclude that both MIT and HIIT limit WD-induced T2DM with diastolic dysfunction and pathological LV hypertrophy, possibly using different adaptive mechanisms.

Pyridoxamine Attenuates Doxorubicin-Induced Cardiomyopathy without Affecting Its Antitumor Effect on Rat Mammary Tumor Cells.

Doxorubicin (DOX) is commonly used in cancer treatment but associated with cardiotoxicity. Pyridoxamine (PM), a vitamin B6 derivative, could be a cardioprotectant. This study investigated the effect of PM on DOX cardiotoxicity and DOX antitumor effectiveness. Sprague Dawley rats were treated intravenously with DOX (2 mg/kg/week) or saline over eight weeks. Two other groups received PM via oral intake (1 g/L in water bottles) next to DOX or saline. Echocardiography was performed after eight weeks. PM treatment significantly attenuated the DOX-induced reduction in left ventricular ejection fraction (72 ± 2% vs. 58 ± 3% in DOX; p < 0.001) and increase in left ventricular end-systolic volume (0.24 ± 0.02 µL/cm2 vs. 0.38 ± 0.03 µL/cm2 in DOX; p < 0.0001). Additionally, LA7 tumor cells were exposed to DOX, PM, or DOX and PM for 24 h, 48 h, and 72 h. Cell viability, proliferation, cytotoxicity, and apoptosis were assessed. DOX significantly reduced LA7 cell viability and proliferation (p < 0.0001) and increased cytotoxicity (p < 0.05) and cleaved caspase-3 (p < 0.001). Concomitant PM treatment did not alter the DOX effect on LA7 cells. In conclusion, PM attenuated DOX-induced cardiomyopathy in vivo without affecting the antitumor effect of DOX in vitro, highlighting PM as a promising cardioprotectant for DOX-induced cardiotoxicity.

Pyridoxamine Limits Cardiac Dysfunction in a Rat Model of Doxorubicin-Induced Cardiotoxicity.

The use of doxorubicin (DOX) chemotherapy is restricted due to dose-dependent cardiotoxicity. Pyridoxamine (PM) is a vitamin B6 derivative with favorable effects on diverse cardiovascular diseases, suggesting a cardioprotective effect on DOX-induced cardiotoxicity. The cardioprotective nature of PM was investigated in a rat model of DOX-induced cardiotoxicity. Six-week-old female Sprague Dawley rats were treated intravenously with 2 mg/kg DOX or saline (CTRL) weekly for eight weeks. Two other groups received PM via the drinking water next to DOX (DOX+PM) or saline (CTRL+PM). Echocardiography, strain analysis, and hemodynamic measurements were performed to evaluate cardiac function. Fibrotic remodeling, myocardial inflammation, oxidative stress, apoptosis, and ferroptosis were evaluated by various in vitro techniques. PM significantly attenuated DOX-induced left ventricular (LV) dilated cardiomyopathy and limited TGF-ß1-related LV fibrotic remodeling and macrophage-driven myocardial inflammation. PM protected against DOX-induced ferroptosis, as evidenced by restored DOX-induced disturbance of redox balance, improved cytosolic and mitochondrial iron regulation, and reduced mitochondrial damage at the gene level. In conclusion, PM attenuated the development of cardiac damage after DOX treatment by reducing myocardial fibrosis, inflammation, and mitochondrial damage and by restoring redox and iron regulation at the gene level, suggesting that PM may be a novel cardioprotective strategy for DOX-induced cardiomyopathy.

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats.

Exercise training is an encouraging approach to treat cardiac dysfunction in type 2 diabetes (T2DM), but the impact of its intensity is not understood. We aim to investigate whether and, if so, how moderate-intensity training (MIT) and high-intensity interval training (HIIT) alleviate adverse cardiac remodeling and dysfunction in rats with T2DM. Male rats received standard chow (n = 10) or Western diet (WD) to induce T2DM. Hereafter, WD rats were subjected to a 12-week sedentary lifestyle (n = 8), running MIT (n = 7) or HIIT (n = 7). Insulin resistance and glucose tolerance were assessed during the oral glucose tolerance test. Plasma advanced glycation end-products (AGEs) were evaluated. Echocardiography and hemodynamic measurements evaluated cardiac function. Underlying cardiac mechanisms were investigated by histology, western blot and colorimetry. We found that MIT and HIIT lowered insulin resistance and blood glucose levels compared to sedentary WD rats. MIT decreased harmful plasma AGE levels. In the heart, MIT and HIIT lowered end-diastolic pressure, left ventricular wall thickness and interstitial collagen deposition. Cardiac citrate synthase activity, mitochondrial oxidative capacity marker, raised after both exercise training modalities. We conclude that MIT and HIIT are effective in alleviating diastolic dysfunction and pathological cardiac remodeling in T2DM, by lowering fibrosis and optimizing mitochondrial capacity.

Acute Exposure to Glycated Proteins Impaired in the Endothelium-Dependent Aortic Relaxation: A Matter of Oxidative Stress.

Chronically increased levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to induce cardiovascular dysfunction. Whether an acute increase in HMW-AGE levels affects vascular function remains unknown. In this study, we examined whether acute exposure to HMW-AGEs disturbs aortic vasomotor function. Aortae were obtained from healthy male rats and were acutely pre-treated with HMW-AGEs in organ baths. Aortic relaxation responses to cumulative doses of acetylcholine (ACh), in the presence or absence of superoxide dismutase (SOD), were measured after precontraction with phenylephrine (PE). Furthermore, levels of 3-nitrotyrosine were evaluated on aortic paraffine sections. In our study, we show that acute exposure to HMW-AGEs significantly decreases the aortic relaxation response to ACh. SOD pre-treatment prevents acute HMW-AGEs-induced impairment by limiting superoxide formation. In conclusion, our data demonstrate that acute exposure to HMW-AGEs causes adverse vascular remodelling, characterised by disturbed vasomotor function due to increased oxidative stress. These results create opportunities for future research regarding the acute role of HMW-AGEs in cardiovascular dysfunction.

Combinational Therapy of Cardiac Atrial Appendage Stem Cells and Pyridoxamine: The Road to Cardiac Repair?

Myocardial infarction (MI) occurs when the coronary blood supply is interrupted. As a consequence, cardiomyocytes are irreversibly damaged and lost. Unfortunately, current therapies for MI are unable to prevent progression towards heart failure. As the renewal rate of cardiomyocytes is minimal, the optimal treatment should achieve effective cardiac regeneration, possibly with stem cells transplantation. In that context, our research group identified the cardiac atrial appendage stem cells (CASCs) as a new cellular therapy. However, CASCs are transplanted into a hostile environment, with elevated levels of advanced glycation end products (AGEs), which may affect their regenerative potential. In this study, we hypothesize that pyridoxamine (PM), a vitamin B6 derivative, could further enhance the regenerative capacities of CASCs transplanted after MI by reducing AGEs' formation. Methods and Results: MI was induced in rats by ligation of the left anterior descending artery. Animals were assigned to either no therapy (MI), CASCs transplantation (MI + CASCs), or CASCs transplantation supplemented with PM treatment (MI + CASCs + PM). Four weeks post-surgery, global cardiac function and infarct size were improved upon CASCs transplantation. Interstitial collagen deposition, evaluated on cryosections, was decreased in the MI animals transplanted with CASCs. Contractile properties of resident left ventricular cardiomyocytes were assessed by unloaded cell shortening. CASCs transplantation prevented cardiomyocyte shortening deterioration. Even if PM significantly reduced cardiac levels of AGEs, cardiac outcome was not further improved. Conclusion: Limiting AGEs' formation with PM during an ischemic injury in vivo did not further enhance the improved cardiac phenotype obtained with CASCs transplantation. Whether AGEs play an important deleterious role in the setting of stem cell therapy after MI warrants further examination.

Advanced Glycation End Products Impair Cardiac Atrial Appendage Stem Cells Properties.

BACKGROUND: During myocardial infarction (MI), billions of cardiomyocytes are lost. The optimal therapy should effectively replace damaged cardiomyocytes, possibly with stem cells able to engraft and differentiate into adult functional cardiomyocytes. As such, cardiac atrial appendage stem cells (CASCs) are suitable candidates. However, the presence of elevated levels of advanced glycation end products (AGEs) in cardiac regions where CASCs are transplanted may affect their regenerative potential. In this study, we examine whether and how AGEs alter CASCs properties in vitro. METHODS AND RESULTS: CASCs in culture were exposed to ranging AGEs concentrations (50 µg/mL to 400 µg/mL). CASCs survival, proliferation, and migration capacity were significantly decreased after 72 h of AGEs exposure. Apoptosis significantly increased with rising AGEs concentration. The harmful effects of these AGEs were partially blunted by pre-incubation with a receptor for AGEs (RAGE) inhibitor (25 µM FPS-ZM1), indicating the involvement of RAGE in the observed negative effects. CONCLUSION: AGEs have a time- and concentration-dependent negative effect on CASCs survival, proliferation, migration, and apoptosis in vitro, partially mediated through RAGE activation. Whether anti-AGEs therapies are an effective treatment in the setting of stem cell therapy after MI warrants further examination.

The Impact of Advanced Glycation End-Products (AGEs) on Proliferation and Apoptosis of Primary Stem Cells: A Systematic Review.

Stem cell-based regenerative therapies hold great promises to treat a wide spectrum of diseases. However, stem cell engraftment and survival are still challenging due to an unfavorable transplantation environment. Advanced glycation end-products (AGEs) can contribute to the generation of these harmful conditions. AGEs are a heterogeneous group of glycated products, nonenzymatically formed when proteins and/or lipids become glycated and oxidized. Our typical Western diet as well as cigarettes contain high AGEs content. AGEs are also endogenously formed in our body and accumulate with senescence and in pathological situations. Whether AGEs have an impact on stem cell viability in regenerative medicine remains unclear, and research on the effect of AGEs on stem cell proliferation and apoptosis is still ongoing. Therefore, this systematic review provides a clear overview of the effects of glycated proteins on cell viability in various types of primary isolated stem cells used in regenerative medicine.

Glycolaldehyde-Derived High-Molecular-Weight Advanced Glycation End-Products Induce Cardiac Dysfunction through Structural and Functional Remodeling of Cardiomyocytes.

BACKGROUND/AIMS: High-molecular-weight advanced glycation end-products (HMW-AGEs) are abundantly present in our Western diet. There is growing evidence reporting that HMW-AGEs contribute to the development of cardiovascular dysfunction in vivo, next to the well-known low-molecular-weight AGEs. The goal of our study is to assess the ultrastructure and function of cardiomyocytes after chronic exposure to HMW-AGEs. A better understanding of underlying mechanisms is essential to create new opportunities for further research on the specific role of HMW-AGEs in the development and progression of cardiovascular diseases. METHODS: Adult male rats were randomly assigned to daily intraperitoneal injection for six weeks with either HMW-AGEs (20 mg/kg/day) or a control solution. Hemodynamic measurements were performed at sacrifice. Single cardiomyocytes from the left ventricle were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Unloaded cell shortening, time to peak and time to 50% relaxation were measured during field stimulation and normalized to diastolic length. L-type Ca2+ current density (ICaL) and steady-state inactivation of ICaL were measured during whole-cell ruptured patch clamp. Myofilament functional properties were measured in membrane-permeabilized cardiomyocytes. Ultrastructural examination of cardiac tissue was performed using electron microscopy. RESULTS: Rats injected with HMW-AGEs displayed in vivo cardiac dysfunction, characterized by significant changes in left ventricular peak rate pressure rise and decline accompanied with an increased heart mass. Single cardiomyocytes isolated from the left ventricle revealed concentric hypertrophy, indicated by the increase in cellular width. Unloaded fractional cell shortening was significantly reduced in cells derived from the HMW-AGEs group and was associated with slower kinetics. Peak L-type Ca2+ current density was significantly decreased in the HMW-AGEs group.L-type Ca2+ channel availability was significantly shifted towards more negative potentials after HMW-AGEs injection. The impact of HMW-AGEs on myofilament function was measured in membrane-permeabilized cardiomyocytes showing a reduction in passive force, maximal Ca2+ activated force and rate of force development. Ultrastructural examination of cardiac tissue demonstrated adverse structural remodeling in HMW-AGEs group characterized by a disruption of the cyto-architecture, a decreased mitochondrial density and altered mitochondrial function. CONCLUSION: Our data indicate that HMW-AGEs induce structural and functional cellular remodeling via a different working mechanism as the well-known LMW-AGEs. Results of our research open the door for new strategies targeting HMW-AGEs to improve cardiac outcome.

Glycolaldehyde-modified proteins cause adverse functional and structural aortic remodeling leading to cardiac pressure overload.

Growing evidence supports the role of advanced glycation end products (AGEs) in the development of diabetic vascular complications and cardiovascular diseases (CVDs). We have shown that high-molecular-weight AGEs (HMW-AGEs), present in our Western diet, impair cardiac function. Whether HMW-AGEs affect vascular function remains unknown. In this study, we aimed to investigate the impact of chronic HMW-AGEs exposure on vascular function and structure. Adult male Sprague Dawley rats were daily injected with HMW-AGEs or control solution for 6 weeks. HMW-AGEs animals showed intracardiac pressure overload, characterized by increased systolic and mean pressures. The contraction response to PE was increased in aortic rings from the HMW-AGEs group. Relaxation in response to ACh, but not SNP, was impaired by HMW-AGEs. This was associated with reduced plasma cyclic GMP levels. SOD restored ACh-induced relaxation of HMW-AGEs animals to control levels, accompanied by a reduced half-maximal effective dose (EC50). Finally, collagen deposition and intima-media thickness of the aortic vessel wall were increased with HMW-AGEs. Our data demonstrate that chronic HMW-AGEs exposure causes adverse vascular remodelling. This is characterised by disturbed vasomotor function due to increased oxidative stress and structural changes in the aorta, suggesting an important contribution of HMW-AGEs in the development of CVDs.

High intensity training improves cardiac function in healthy rats.

Exercise training is a low cost and safe approach for reducing the risk of cardiovascular disease development. Currently, moderate-intensity training (MIT) is the most preferred exercise type. However, high-intensity interval training (HIIT) is gaining interest especially among athletes and healthy individuals. In this study, we examined cardiac remodeling resulting from MIT and HIIT in healthy rats. Healthy male Sprague-Dawley rats were randomly assigned to MIT or HIIT for 13 weeks. Animals kept sedentary (SED) were used as control. Cardiac function was evaluated with echocardiography and hemodynamic measurements. Heart tissue was stained for capillary density and fibrosis. After 13 weeks of training, only HIIT induced beneficial cardiac hypertrophy. Overall global cardiac parameters (such as ejection fraction, cardiac output and volumes) were improved similarly between both training modalities. At tissue level, collagen content was significantly and similarly reduced in both exercise groups. Finally, only HIIT increased significantly capillary density. Our data indicate that even if very different in design, HIIT and MIT appear to be equally effective in improving cardiac function in healthy rats. Furthermore, HIIT provides additional benefits through improved capillary density and should therefore be considered as a preferred training modality for athletes and for patients.

Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity.

NEW FINDINGS: What is the central question of this study? Does acute exposure to high molecular weight advanced glycation end products (HMW-AGEs) alter cardiomyocyte contractile function? What is the main finding and its importance? Ventricular cardiomyocytes display reduced Ca2+ influx, resulting in reduced contractile capacity, after acute exposure to HMW-AGEs, independent of activation of their receptor. Given that HMW-AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds. ABSTRACT: Sustained elevated levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW-AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre-incubated with or without an anti-RAGE antibody. Unloaded cell shortening and L-type Ca2+ current amplitude were evaluated in the presence or absence of HMW-AGEs (200 µg ml-1 ). Expression of RAGE, c-Jun N-terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW-AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca2+ influx. These alterations were also observed in cardiomyocytes pre-incubated with anti-RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW-AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation.

Western diet given to healthy rats mimics the human phenotype of diabetic cardiomyopathy.

Diabetes mellitus (DM) is a major problem worldwide. Within this patient group, cardiovascular diseases are the biggest cause of morbidity and mortality. Diabetic cardiomyopathy (DCM) is defined as diabetes-associated structural and functional changes in the myocardium, not directly attributable to other confounding factors such as coronary artery disease or hypertension. Pathophysiology of DCM remains unclear due to a lack of adequate animal models reflecting the current pandemic of diabetes, associated with a high increased sugar intake and the 'Western' lifestyle. The aim of this study was to develop an animal model mimicking this 'Western' lifestyle causing a human-like phenotype of DCM. Twenty-four Sprague-Dawley rats were randomly assigned into a normal or a 'Western' diet group for 18 weeks. Glucose and insulin levels were measured with an OGTT. Heart function was assessed by echocardiography and hemodynamic measurements in vivo. Cardiac fibrosis and inflammation were investigated in vitro. 'Western' diet given to healthy rats for 18 weeks induced hyperglycemia together with increased AGEs levels, insulin levels and hypertriglyceridemia. Heart function was altered with increased end-diastolic pressure, left ventricle hypertrophy. Changes in vivo were associated with increased collagen deposition and increased PAI-1 levels in the heart. High-sugar diet or 'Western' diet causes T2DM and the hallmarks of DCM in rats, reflecting the phenotype of the disease seen in patients. Using this new model of T2DM with DCM might open new insight in understanding the pathophysiology of DCM and on a long term, test targeted therapies for T2DM with DCM patients.

Pyridoxamine improves survival and limits cardiac dysfunction after MI.

Advanced glycation end products (AGEs) play a key role in the progression of heart failure. Whether treatments limiting AGEs formation would prevent adverse left ventricular remodeling after myocardial infarction (MI) remain unknown. We investigated whether pyridoxamine (PM) could limit adverse cardiac outcome in MI. Rats were divided into MI, MI + PM and Sham. Echocardiography and hemodynamic parameters were used to assess cardiac function 8 weeks post-surgery. Total interstitial collagen, collagen I and collagen III were quantified using Sirius Red and polarized light microscopy. PM improved survival following LAD occlusion. Pre-treatment with PM significantly decreased the plasma AGEs levels. MI rats treated with PM displayed reduced left ventricular end-diastolic pressure and tau compared to untreated MI rats. Deformation parameters were also improved with PM. The preserved diastolic function was related to the reduced collagen content, in particular in the highly cross-linked collagen type I, mainly in the peri-infarct region, although not via TGF-ß1 pathway. Our data indicate that PM treatment prevents the increase in AGEs levels and reduces collagen levels in a rat model of MI, resulting in an improved cardiac phenotype. As such, therapies targeting formation of AGEs might be beneficial in the prevention and/or treatment of maladaptive remodeling following MI.

Advanced glycation end products (AGEs) and cardiovascular dysfunction: focus on high molecular weight AGEs.

Advanced glycation end products (AGEs) are a group of proteins and lipids becoming glycated and oxidized after persistent contact with reducing sugars or short-chain aldehydes with amino group and/or high degree of oxidative stress. The accumulation of AGEs in the body is a natural process that occurs with senescence, when the turnover rate of proteins is reduced. However, increased circulating AGEs have been described to arise at early lifetime and are associated with adverse outcome and survival, in particular in settings of cardiovascular diseases. AGEs contribute to the development of cardiac dysfunction by two major mechanisms: cross-linking of proteins or binding to their cell surface receptor. Recently, growing evidence shows that high-molecular weight AGEs (HMW-AGEs) might be as important as the characterized low-molecular weight AGEs (LMW-AGEs). Here, we point out the targets of AGEs in the heart and the mechanisms that lead to heart failure with focus on the difference between LMW-AGEs and the less characterized HMW-AGEs. As such, this review is a compilation of relevant papers in the form of a useful resource tool for researchers who want to further investigate the role of HMW-AGEs on cardiac disorders and need a solid base to start on this specific topic.

Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction?

BACKGROUND: Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction. METHODS: Healthy rats were daily ip injected with 20mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot. RESULTS: After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-α and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression. CONCLUSION: Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function.

Exercise improves cardiac function and attenuates insulin resistance in Dahl salt-sensitive rats.

BACKGROUND: The development of heart failure (HF) secondary to hypertension is a complex process related to a series of physiological and molecular factors including glucose dysregulation. The overall objective of this study was to investigate whether exercise training could improve cardiac function and insulin resistance in a rat model of hypertensive HF. METHODS: Seven week old Dahl salt-sensitive rats received either 8% NaCl (n = 30) or 0.3% NaCl (n = 18) diet. After a 5-week diet, animals were randomly assigned to exercise training (treadmill running at 18 m/min, 5% inclination for 60 min, 5 days/week) or kept sedentary for 6 additional weeks. 2D echocardiography was used to calculate left ventricular (LV) dimensions, volumes and global functional parameters. LV global deformation parameters were measured with speckle tracking echocardiography. Insulin resistance was assessed using 1h oral glucose tolerance testing. RESULTS: High salt diet led to cardiac hypertrophy and HF, characterized by increased wall thicknesses and LV volumes as well as reduced deformation parameters. In addition, high salt diet was associated with the development of insulin resistance. Exercise training improved cardiac function, reduced the extent of interstitial fibrosis and reduced insulin levels 60 min post-glucose administration. CONCLUSIONS: Even if not fully reversed, exercise training in HF animals improved cardiac function and insulin resistance. Adjusted modalities of exercise training might offer new insights not only as a preventive strategy, but also as a treatment for HF patients.