Enhancing the understanding of abstract neurophysiology concepts by first-year students at the University of La Réunion.

Teaching physiology can be challenging as students are initially required to understand basic and abstract concepts. Thus, students typically view physiology as a 'difficult' subject and place an emphasis on rote learning and memorization. Here, we attempted to address this knowledge gap by introducing a pedagogical intervention into the neurophysiology lesson plan of first-year medical and health physiology students at the University of La Réunion. This intervention aimed to better link abstract concepts (e.g. saltatory conduction) and a pathological disorder (multiple sclerosis), together with a discussion of a specific therapeutic intervention (fampridine). Students were required to complete readings (focused on neurophysiology aspects) and two online quizzes before two scheduled in-person lectures. They could also pose questions on a dedicated online forum. Thereafter, the in-person lectures discussed questions posted on the online forum, provided feedback on poorly answered questions (from the online quizzes), and dealt with questions posed by students attending classes. Student feedback regarding the pedagogic intervention was assessed by an anonymous online survey. This survey revealed that the pedagogical intervention was positively received. For example, 94% of respondents agreed the course was well developed, while 80% indicated that the pedagogical intervention was beneficial in terms of their understanding of basic and abstract neurophysiology concepts. Together, this pedagogical intervention was enthusiastically received by the students who better understood how basic nerve physiology concepts fit into the broader context, and that such an understanding can result in the development and the roll-out of unique therapeutic interventions for multiple sclerosis.

Glial cell activity in cardiovascular diseases and risk of acute myocardial infarction.

Growing evidence indicates that the pathophysiological link between the brain and heart underlies cardiovascular diseases, specifically acute myocardial infarction (AMI). Astrocytes are the most abundant glial cells in the central nervous system and provide support/protection for neurons. Astrocytes and peripheral glial cells are emerging as key modulators of the brain-heart axis in AMI, by affecting sympathetic nervous system activity (centrally and peripherally). This review, therefore, aimed to gain an improved understanding of glial cell activity and AMI risk. This includes discussions on the potential role of contributing factors in AMI risk, i.e., autonomic nervous system dysfunction, glial-neurotrophic and ischemic risk markers [glial cell line-derived neurotrophic factor (GDNF), astrocytic S100 calcium-binding protein B (S100B), silent myocardial ischemia, and cardiac troponin T (cTnT)]. Consideration of glial cell activity and related contributing factors in certain brain-heart disorders, namely, blood-brain barrier dysfunction, myocardial ischemia, and chronic psychological stress, may improve our understanding regarding the pathological role that glial dysfunction can play in the development/onset of AMI. Here, findings demonstrated perturbations in glial cell activity and contributing factors (especially sympathetic activity). Moreover, emerging AMI risk included sympathovagal imbalance, low GDNF levels reflecting prothrombic risk, hypertension, and increased ischemia due to perfusion deficits (indicated by S100B and cTnT levels). Such perturbations impacted blood-barrier function and perfusion that were exacerbated during psychological stress. Thus, greater insights and consideration regarding such biomarkers may help drive future studies investigating brain-heart axis pathologies to gain a deeper understanding of astrocytic glial cell contributions and unlock potential novel therapies for AMI.

Can the introduction of an authentic learning exercise lead to the modulation of breakfast behavior in undergraduate students at University of La Réunion?

The authentic teaching and learning approach introduces real-world scenarios into the classroom to better engage Generation Z students. Considering this, we introduced an authentic learning practical exercise (breakfast meal and glycemic variation) to undergraduate biology students at the University of La Réunion (France). Here, students were initially briefed regarding the practical and subsequently determined their baseline glucose values (glucometer). They then consumed 200 mL of fruit juice together with a pain au chocolat (chocolate pastry) and subsequently recorded their glucose values at regular intervals. The last reading was done after 150 min, and they thereafter plotted such data to reveal temporal glycemic variations. During this time, the students also worked on a report to document information collected and began to supply responses to several listed questions. Three weeks after completion of the practical, we evaluated whether this intervention would lead to changes in their views regarding the nature and regularity of breakfast meal intake (employing survey questions). Our findings show that a reasonable proportion of the students indicated that the intervention did change their dietary habits, with 50% sometimes opting for an improved breakfast, whereas 10% also changed their habits albeit for only a small while. Of note, >60% of students indicated that they changed their breakfast intake habits by the end of the endocrinology module. These findings show that the beneficial effects of authentic teaching approaches may elicit relatively long-lasting changes in terms of breakfast behavioral patterns in young people and that such effects may also impact the broader society.NEW & NOTEWORTHY This study introduced an authentic learning exercise (endocrinology practical exercise) to undergraduate biology students and ascertained whether it changed their views regarding the nature and regularity of breakfast meals. Here, many altered their breakfast dietary habits, which persisted even after the completion of their module. Authentic teaching approaches can therefore trigger relatively long-lasting changes in terms of breakfast behavioral patterns in young people and may also impact the broader society.

The implementation of active learning practices in a South African physiology class: a follow-up study.

Although there is increased uptake of active learning approaches in especially developed countries, this is still lagging within the African context. The current study therefore focused on the implementation of group learning at Stellenbosch University, with several modifications versus our earlier, pilot study. Students freely formed small groups at the start of a 5-wk cardiovascular physiology lecture series and were apportioned three separate assignments to complete over this period. This included three in-class group-learning sessions, while students also completed group work outside class times. The active learning element was embedded within a constructive alignment framework. Our data revealed that 75% of the students felt that the in-class sessions was a good use of their time and that they progressively improved their assignment scores, i.e., 67.5 ± 9.3%, 72.4 ± 9.8%, and 76.1 ± 9.5% for the first, second, and final ones, respectively (P < 0.0001). Moreover, the average class score for their final test (68 ± 15.1%) was higher when compared with the average class score (57.5 ± 19.4%) calculated for the previous 3 yr (P < 0.0001). This study revealed two major findings: i.e., 1) students displayed a strong positive response regarding the adoption of in-class collaborative group work, and 2) the introduction of such active learning elements correlated with improved student assignment and test scores. Based on these findings, we propose additional modifications (including a shift to more formative assessments) to ensure even greater success with the roll-out of such active learning elements within the African context.

Chronic stress and endothelial dysfunction: mechanisms, experimental challenges, and the way ahead.

Although chronic stress is an important risk factor for cardiovascular diseases (CVD) onset, the underlying mechanisms driving such pathophysiological complications remain relatively unknown. Here, dysregulation of innate stress response systems and the effects of downstream mediators are strongly implicated, with the vascular endothelium emerging as a primary target of excessive glucocorticoid and catecholamine action. Therefore, this review article explores the development of stress-related endothelial dysfunction by focusing on the following: 1) assessing the phenomenon of stress and complexities surrounding this notion, 2) discussing mechanistic links between chronic stress and endothelial dysfunction, and 3) evaluating the utility of various preclinical models currently employed to study mechanisms underlying the onset of stress-mediated complications such as endothelial dysfunction. The data reveal that preclinical models play an important role in our efforts to gain an increased understanding of mechanisms underlying stress-mediated endothelial dysfunction. It is our understanding that this provides a good foundation going forward, and we propose that further efforts should be made to 1) more clearly define the concept of stress and 2) standardize protocols of animal models with specific guidelines to better indicate the mental complications that are simulated.

HIV-related cardiovascular diseases: the search for a unifying hypothesis.

Although the extensive rollout of antiretroviral (ARV) therapy resulted in a longer life expectancy for people living with human immunodeficiency virus (PLHIV), such individuals display a relatively increased occurrence of cardiovascular diseases (CVD). This health challenge stimulated significant research interests in the field, leading to an improved understanding of both lifestyle-related risk factors and the underlying mechanisms of CVD onset in PLHIV. However, despite such progress, the precise role of various risk factors and mechanisms underlying the development of HIV-mediated CVD still remains relatively poorly understood. Therefore, we review CVD onset in PLHIV and focus on 1) the spectrum of cardiovascular complications that typically manifest in such persons and 2) underlying mechanisms that are implicated in this process. Here, the contributions of such factors and modulators and underlying mechanisms are considered in a holistic and integrative manner to generate a unifying hypothesis that includes identification of the core pathways mediating CVD onset. The review focuses on the sub-Saharan African context, as there are relatively high numbers of PLHIV residing within this region, indicating that the greater CVD risk will increasingly threaten the well-being and health of its citizens. It is our opinion that such an approach helps point the way for future research efforts to improve treatment strategies and/or lifestyle-related modifications for PLHIV.

Student response to a cooperative learning element within a large physiology class setting: lessons learned.

Physiology students grapple with large amounts of subject content and hence memorize facts to pass examinations. In parallel, students display limited critical-thinking and creative skills, integration abilities, and/or a deeper engagement with subject content. This study aimed to assess the feasibility of introducing active learning methods (cooperative learning) in a relatively large class to final-year undergraduate physiology students (Bachelor of Science stream) at Stellenbosch University in South Africa. An assignment designed to enhance active and engaged learning was made available to the students (n = 225) during the second week of a 5-wk cardiovascular physiology series of lectures. Students were instructed to freely form working groups (n = 3/group) and the assignment was due by the end of the module. Student groups were expected and encouraged to continuously work on the assignment (outside class time). Three cooperative learning slots were also created during class time, with the lecturer and postgraduate students acting as guides. After the module, students anonymously completed an electronic questionnaire. This study revealed three major findings in terms of implementing cooperative learning in large classes within a South African context, i.e., 1) relatively good reception by students with some indication of group work; 2) it is logistically feasible in relatively large classes, although adequate support is crucial; and 3) additional measures need to be adopted to ensure its success.

HIV and Cardiovascular Disease: Role of Immunometabolic Perturbations.

The successful rollout of anti-retroviral therapy ensured that HIV is increasingly managed as a chronic condition. HIV-positive persons are therefore exhibiting increased cardiovascular complications. This review focuses on the emerging role of "immunometabolism" within the context of HIV-related immune dysregulation and cardiovascular disease onset. Here, persistent immune activation contributes to pathophysiological perturbations during early infection, resulting in immune cell metabolic reprogramming and the activation of coagulation pathways in HIV-positive individuals.

HIV and cardiovascular diseases risk: exploring the interplay between T-cell activation, coagulation, monocyte subsets, and lipid subclass alterations.

Although rollout of combined antiretroviral treatment (cART) has blunted human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) onset, there is increased development of cardiovascular diseases (CVDs) in HIV-infected individuals. While most HIV-infected individuals on cART achieve viral suppression, this may not necessarily result in complete immunological recovery. This study therefore evaluated T-cell-mediated changes and coagulation markers in HIV-positive individuals to ascertain their potential to increase CVD risk. Eighty participants were recruited (Worcester, South Africa), and fasted blood was collected to evaluate: 1) immune activation (CD38 expression on CD4+ and CD8+ T cells) and thrombus formation [tissue factor (CD142)] on CD4+ and CD8+ T cells; 2) monocyte subpopulations (nonclassical, intermediate, and classical); and 3) classical regulatory T (Treg) cells with activation markers [glycoprotein A repetitions predominant (GARP) and special AT-rich sequence-binding protein 1 (SATB-1)]. High- and low-density lipoprotein subclasses (Lipoprint) were also determined. This study revealed four key findings for HIV-positive patients: 1) coexpression of the CD142 coagulation marker together with immune activation on both CD4+ and CD8+ T cells during chronic infection stages; 2) Treg cell activation and upregulated GARP and SATB-1 contributing to Treg dysfunction in chronic HIV; 3) proatherogenic monocyte subset expansion with significant correlation between T-cell activation and macrophage activation (marker: CD163); and 4) significant correlation between immune activation and lipid subclasses, revealing crucial changes that can be missed by traditional lipid marker assessments (LDL and HDL). These data also implicate lipopolysaccharide-binding protein as a crucial link between immune activation, lipid alterations, and increased CVD risk. NEW & NOTEWORTHY With combined antiretroviral treatment rollout, HIV-AIDS patients are increasingly associated with cardiovascular diseases onset. This study demonstrated the significant interplay between adaptive immune cell activation and monocyte/macrophage markers in especially HIV-positive individuals with virological failure and on second line treatment. Our data also show a unique link between immune activation and lipid subclass alterations, revealing important changes that can be missed by traditional lipid marker assessments (e.g., LDL and HDL).

Health Benefits of Fasting and Caloric Restriction.

PURPOSE OF REVIEW: Obesity and obesity-related diseases, largely resulting from urbanization and behavioral changes, are now of global importance. Energy restriction, though, is associated with health improvements and increased longevity. We review some important mechanisms related to calorie limitation aimed at controlling of metabolic diseases, particularly diabetes. RECENT FINDINGS: Calorie restriction triggers a complex series of intricate events, including activation of cellular stress response elements, improved autophagy, modification of apoptosis, and alteration in hormonal balance. Intermittent fasting is not only more acceptable to patients, but it also prevents some of the adverse effects of chronic calorie restriction, especially malnutrition. There are many somatic and potentially psychologic benefits of fasting or intermittent calorie restriction. However, some behavioral modifications related to abstinence of binge eating following a fasting period are crucial in maintaining the desired favorable outcomes.

Cardiovascular risk and endothelial function in people living with HIV/AIDS: design of the multi-site, longitudinal EndoAfrica study in the Western Cape Province of South Africa.

BACKGROUND: There is growing evidence of an interaction between HIV-infection, anti-retroviral therapy (ART) and cardiovascular diseases (CVD). Epidemiological studies in Europe and North America have been observing a shift towards an increased incidence of coronary heart disease and acute myocardial infarctions in HIV-infected populations compared to the general population even after adjusting for traditional cardiovascular risk factors. Despite South Africa (and sub-Saharan Africa, SSA) being regarded as the epicentre of the global HIV epidemic, very little is known about the prevalence of cardiovascular risk factors and precursors of vascular disease in HIV-infected populations in this region. The knowledge gap is further widened by the paucity of data from prospective studies. We present the rationale, objectives and key methodological features of the EndoAfrica study, which aims to determine whether HIV-infection and ART are associated with altered cardiovascular risk and changes in vascular endothelial structure and function in adults living in the Western Cape Province of South Africa. METHODS: In this longitudinal study, comprehensive cardiovascular assessments of HIV-negative and HIV-positive (with and without ART) study participants are performed by clinical and biochemical screening for traditional cardiovascular risk factors and biomarkers of CVD. Vascular and endothelial function is determined by brachial artery flow-mediated dilatation (FMD), carotid-intima-thickness (IMT) measurements and quantitative retinal blood vessel analyses, complemented by vascular endothelial biomarker assays. Finally, we aim to statistically determine whether HIV-infection and/or ART are associated with increased cardiovascular risk and vascular endothelial dysfunction, and determine whether there is progression/regression in these endpoints 18 months after the baseline assessments. DISCUSSION: The EndoAfrica study provides a unique opportunity to recruit a cohort of HIV-infected patients and HIV-negative controls who will be comprehensively and longitudinally assessed for cardiovascular risk and disease profile with vascular endothelial function as a potentially important intermediate cardiovascular phenotype. To our knowledge, it is the first time that such a systematic study has been established in the context of SSA and South Africa.

Age-dependent development of left ventricular wall thickness in type 2 diabetic (db/db) mice is associated with elevated low-density lipoprotein and triglyceride serum levels.

Diabetic cardiomyopathy (DCM) is a disease of heart muscle that remains one of the leading causes of death in diabetic individuals. Shifts in substrate preference resulting in aberrant serum lipid content and enlarged left ventricular wall thickness are well-established characteristics associated with the development of DCM. As underlying mechanisms driving the onset of the DCM remain relatively unclear, this study sought to characterize age-dependent development of left ventricular (LV) wall thickness in diabetic (db/db) mice. Such data were compared with low-density lipoprotein (LDL) and triglyceride serum levels to assess whether any correlation exists between the parameters here investigated. For methods, db/db mice together with nondiabetic controls (n = six per group) were monitored from the age of 6-16 weeks. Mice were terminated each week to measure body weights, heart weights, liver weights, tibia length, and fasting plasma glucose levels. Heart tissues were stained with haematoxylin and eosin to measure LV wall and interventricular septum thickness together with an assessment of myocardial remodeling. Serum was collected weekly and used to measure LDL and triglyceride levels. Results showed that db/db mice presented significantly increased body weights, liver/body weight, and fasting plasma glucose levels from the age of 6-16 weeks. They further displayed a marked enlargement of LV wall and interventricular septum thickness from the age of 11 weeks, while increased heart weight/tibia length was recorded only from week 16. From week 11, the LV wall and interventricular septum thickness results corresponded with cardiac remodeling and raised LDL and triglyceride serum levels. In summary, age-dependent development of LV wall thickness in db/db mice is partially associated with increased LDL and triglyceride levels, elucidating a potential pathophysiological mechanism.

The Transcription Profile Unveils the Cardioprotective Effect of Aspalathin against Lipid Toxicity in an In Vitro H9c2 Model.

Aspalathin, a C-glucosyl dihydrochalcone, has previously been shown to protect cardiomyocytes against hyperglycemia-induced shifts in substrate preference and subsequent apoptosis. However, the precise gene regulatory network remains to be elucidated. To unravel the mechanism and provide insight into this supposition, the direct effect of aspalathin in an isolated cell-based system, without the influence of any variables, was tested using an H9c2 cardiomyocyte model. Cardiomyocytes were exposed to high glucose (33 mM) for 48 h before post-treatment with or without aspalathin. Thereafter, RNA was extracted and RT2 PCR Profiler Arrays were used to profile the expression of 336 genes. Results showed that, 57 genes were differentially regulated in the high glucose or high glucose and aspalathin treated groups. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis revealed lipid metabolism and molecular transport as the biological processes altered after high glucose treatment, followed by inflammation and apoptosis. Aspalathin was able to modulate key regulators associated with lipid metabolism (Adipoq, Apob, CD36, Cpt1, Pparγ, Srebf1/2, Scd1 and Vldlr), insulin resistance (Igf1, Akt1, Pde3 and Map2k1), inflammation (Il3, Il6, Jak2, Lepr, Socs3, and Tnf13) and apoptosis (Bcl2 and Chuk). Collectively, our results suggest that aspalathin could reverse metabolic abnormalities by activating Adipoq while modulating the expression of Pparγ and Srebf1/2, decreasing inflammation via Il6/Jak2 pathway, which together with an observed increased expression of Bcl2 prevents myocardium apoptosis.

Aspalathin Protects the Heart against Hyperglycemia-Induced Oxidative Damage by Up-Regulating Nrf2 Expression.

Aspalathin (ASP) can protect H9c2 cardiomyocytes against high glucose (HG)-induced shifts in myocardial substrate preference, oxidative stress, and apoptosis. The protective mechanism of ASP remains unknown. However, as one of possible, it is well known that phytochemical flavonoids reduce oxidative stress via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation resulting in up-regulation of antioxidant genes and enzymes. Therefore, we hypothesized that ASP protects the myocardium against HG- and hyperglycemia-induced oxidative damage by up-regulating Nrf2 expression in H9c2 cardiomyocytes and diabetic (db/db) mice, respectively. Using an oxidative stress RT² Profiler PCR array, ASP at a dose of 1 µM was demonstrated to protect H9c2 cardiomyocytes against HG-induced oxidative stress, but silencing of Nrf2 abolished this protective response of ASP and exacerbated cardiomyocyte apoptosis. Db/db mice and their non-diabetic (db/+) littermate controls were subsequently treated daily for six weeks with either a low (13 mg/kg) or high (130 mg/kg) ASP dose. Compared to nondiabetic mice the db/db mice presented increased cardiac remodeling and enlarged left ventricular wall that occurred concomitant to enhanced oxidative stress. Daily treatment of mice with ASP at a dose of 130 mg/kg for six weeks was more effective at reversing complications than both a low dose ASP or metformin, eliciting enhanced expression of Nrf2 and its downstream antioxidant genes. These results indicate that ASP maintains cellular homeostasis and protects the myocardium against hyperglycemia-induced oxidative stress through activation of Nrf2 and its downstream target genes.

Damaging effects of hyperglycemia on cardiovascular function: spotlight on glucose metabolic pathways.

The incidence of cardiovascular complications associated with hyperglycemia is a growing global health problem. This review discusses the link between hyperglycemia and cardiovascular diseases onset, focusing on the role of recently emerging downstream mediators, namely, oxidative stress and glucose metabolic pathway perturbations. The role of hyperglycemia-mediated activation of nonoxidative glucose pathways (NOGPs) [i.e., the polyol pathway, hexosamine biosynthetic pathway, advanced glycation end products (AGEs), and protein kinase C] in this process is extensively reviewed. The proposal is made that there is a unique interplay between NOGPs and a downstream convergence of detrimental effects that especially affect cardiac endothelial cells, thereby contributing to contractile dysfunction. In this process the AGE pathway emerges as a crucial mediator of hyperglycemia-mediated detrimental effects. In addition, a vicious metabolic cycle is established whereby hyperglycemia-induced NOGPs further fuel their own activation by generating even more oxidative stress, thereby exacerbating damaging effects on cardiac function. Thus NOGP inhibition, and particularly that of the AGE pathway, emerges as a novel therapeutic intervention for the treatment of cardiovascular complications such as acute myocardial infarction in the presence hyperglycemia.

Enhanced oxidative stress in adipose tissue from diabetic mice, possible contribution of glycated albumin.

Although enhanced oxidative stress and proteotoxicity constitute major contributors to the pathogenesis of multiple diseases, there is limited understanding of its role in adipose tissue. Here, we aimed at evaluating oxidative stress biomarkers in adipocytes from diabetic/obese db/db mice. The current study revealed that reactive oxygen species production was upregulated in adipocytes, together with lipid peroxidation 4-hydroxynonenal accumulation, and altered proteolytic and antioxidant activities. In parallel, acute exposure of 3T3L1 adipocyte cell lines to glycated albumin (known to be enhanced with diabetes) also elicited intracellular free radical formation. Our data provide novel insights into redox and proteolytic homeostasis in adipocytes.

Phenylpyruvic Acid-2-O-ß-D-Glucoside Attenuates High Glucose-Induced Apoptosis in H9c2 Cardiomyocytes.

Chronic hyperglycemia is closely associated with impaired substrate metabolism, dysregulated mitochondrial membrane potential, and apoptosis in the diabetic heart. As adult cardiomyocytes display a limited capacity to regenerate following an insult, it is essential to protect the myocardium against the detrimental effects of chronic hyperglycemia. This study therefore investigated whether phenylpyruvic acid-2-O-ß-D-glucoside, present in Aspalathus linearis (rooibos), is able to attenuate hyperglycemia-induced damage in H9c2 cardiomyocytes. H9c2 cardiomyocytes were exposed to a high glucose concentration (33 mM) prior to treatment with phenylpyruvic acid-2-O-ß-D-glucoside (1 µM), metformin (1 µM), or a combination of phenylpyruvic acid-2-O-ß-D-glucoside and metformin (both at 1 µM). Our data revealed that high glucose exposure increased cardiac free fatty acid uptake and oxidation, mitochondrial membrane potential, and apoptosis (caspase 3/7 activity and TUNEL), and decreased the Bcl2/Bax protein expression ratio. Phenylpyruvic acid-2-O-ß-D-glucoside treatment, alone or in combination with metformin, attenuated these glucose-induced perturbations, confirming its protective effect in H9c2 cardiomyocytes exposed to chronic hyperglycemia.

HIV protease inhibitors and onset of cardiovascular diseases: a central role for oxidative stress and dysregulation of the ubiquitin-proteasome system.

The successful roll-out of highly active antiretroviral therapy (HAART) has extended life expectancy and enhanced the overall well-being of HIV-positive individuals. There are, however, increased concerns regarding HAART-mediated metabolic derangements and its potential risk for cardiovascular diseases (CVD) in the long-term. Here certain classes of antiretroviral drugs such as the HIV protease inhibitors (PIs) are strongly implicated in this process. This article largely focuses on the direct PI-linked development of cardio-metabolic complications, and reviews the inter-linked roles of oxidative stress and the ubiquitin-proteasome system (UPS) as key mediators driving this process. It is proposed that PIs trigger reactive oxygen species (ROS) production that leads to serious downstream consequences such as cell death, impaired mitochondrial function, and UPS dysregulation. Moreover, we advocate that HIV PIs may also directly lower myocardial UPS function. The attenuation of cardiac UPS can initiate transcriptional changes that contribute to perturbed lipid metabolism, thereby fueling a pro-atherogenic milieu. It may also directly alter ionic channels and interfere with electrical signaling in the myocardium. Therefore HIV PI-induced ROS together with a dysfunctional UPS elicit detrimental effects on the cardiovascular system that will eventually result in the onset of heart diseases. Thus while HIV PIs substantially improve life expectancy and quality of life in HIV-positive patients, its longer-term side-effects on the cardiovascular system should lead to a) greater clinical awareness regarding its benefit-harm paradigm, and b) the development and evaluation of novel co-treatment strategies.

Partial inhibition of the ubiquitin-proteasome system ameliorates cardiac dysfunction following ischemia-reperfusion in the presence of high glucose.

BACKGROUND: Acute hyperglycemia co-presenting with myocardial infarction (in diabetic and non-diabetic individuals) is often associated with a poor prognosis. Although acute hyperglycemia induces oxidative stress that can lead to dysregulation of the ubiquitin-proteasome system (UPS), it is unclear whether increased/decreased UPS is detrimental with ischemia-reperfusion under such conditions. As our earlier data implicated the UPS in cardiac damage, we hypothesized that its inhibition results in cardioprotection with ischemia-reperfusion performed under conditions that simulate acute hyperglycemia. METHODS: Ex vivo rat heart perfusions were performed with Krebs-Henseleit buffer containing 33 mM glucose vs. controls (11 mM glucose) for 60 min stabilization, followed by 20 min global ischemia and 60 min reperfusion ± 5 µM lactacystin and 10 µM MG-132, respectively. The UPS inhibitors were added during the first 20 min of the reperfusion phase and various cardiac functional parameters evaluated. In parallel experiments, infarct sizes were assessed following 20 min regional ischemia and 120 min reperfusion ± each of the respective UPS inhibitors (added during reperfusion). Heart tissues were collected and analyzed for markers of oxidative stress, UPS activation, inflammation and autophagy. RESULTS: The proteasome inhibitor doses and treatment duration here employed resulted in partial UPS inhibition during the reperfusion phase. Both lactacystin and MG-132 administration resulted in cardioprotection in our experimental system, with MG-132 showing a greater effect. The proteasome inhibitors also enhanced cardiac superoxide dismutase protein levels (SOD1, SOD2), attenuated pro-inflammatory effects and caused an upregulation of autophagic markers. CONCLUSIONS: This study established that partial proteasome inhibition elicits cardioprotection in hearts exposed to ischemia-reperfusion with acute simulated hyperglycemia. These data reveal that protease inhibition triggered three major protective effects, i.e. (a) enhancing myocardial anti-oxidant defenses, (b) attenuating inflammation, and (c) increasing the autophagic response. Thus the UPS emerges as a unique therapeutic target for the treatment of ischemic heart disease under such conditions.