Michal Horowitz

• Hebrew University of Jerusalem

Septic peritonitis (SP) is a life-threating condition. Extracellular histones exert cytotoxic, prothrombotic and proinflammatory effects. Determining prognosis for dogs suffering from SP remains challenging. Our objective was to investigate serum general histones concentrations (sHs) as biomarkers of disease severity and outcome in dogs with natura...

1) The first evidence of the beneficial impact of Long-Term-Heat-Acclimation (LTHA) on cardio-vascular compliance was the positive inotropic response and improved left ventricular (LV) compliance noted when isolated hearts from LTHA rats were studied. Human echo study demonstrates that passive HA affects the right ventricle and the atria as well. 2...

This chapter will cover the historical development of thermoregulatory studies in Israel since the establishment of The Hebrew University of Jerusalem in 1925, and will attempt to dissect the influences that led to the development of the various research disciplines. Annotations to earlier studies in our area are briefly provided. In parallel with...

Purpose Exercise is a valuable intervention modality for patients post-myocardial infarction (MI). Aerobic and resistance training are both commonly used separately in cardiac rehabilitation. However, the effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac electrophysiol...

Exposure to high ambient temperature is a stressor that influences both biological and behavioral functions and has been previously shown to have an extensive impact on brain structure and function. Physiological, cellular and behavioral responses to heat-stress (HS) (40–41 °C, 2 h) were evaluated in adult male Sprague-Dawley rats. The effect of HS...

New findings: What is the topic of this review? This review outlines the history of research on epigenetic adaptations to heat exposure. The perspective taken is that adaptations reflect properties of hormesis, where low, repeated doses of heat induce adaptation (acclimation/acclimatization); whereas, brief, life-threatening exposures can induce m...

The effect of 30 days of β-alanine supplementation on neurophysiological responses of animals exposed to an acute heat stress (HS) was examined. Animals were randomized to one of three groups; exposed to HS (120 min at 40–41 °C) and fed a normal diet (EXP; n = 12); EXP and supplemented with β-alanine (EXP + BA; n = 10); or not exposed (CTL; n = 10)...

Traumatic brain injury (TBI), caused by mechanical impact to the brain, is a leading cause of death and disability among young adults, with slow and often incomplete recovery. Preemptive treatment strategies may increase the injury resilience of high-risk populations such as soldiers and athletes. In this work, the xanthophyll carotenoid Astaxanthi...

Heat acclimation (HA) induces metabolic plasticity to resist the effects of environmental heat with cross-tolerance to novel stressors such as oxygen supply perturbations, exercise, and alike. Our previous results indicated that hypoxia inducible transcription factor (HIF-1α) contributes to this adaptive process. In the present study, we link funct...

Objectives The effect of 30-days of β-alanine (BA) supplementation on heat shock protein 70 (HSP70), inflammatory and neurotrophin responses in the hippocampus and hypothalamus of rats exposed to an acute heat stress was investigated. Methods Animals were randomized to either a control (CTL) group or BA supplementation (100mg·kg−1) group. All anim...

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Astaxanthin is a powerful carotenoid antioxidant prevalent in marine organisms and approved as a food supplement. Recent studies have demonstrated Astaxanthin’s beneficial attributes in various health states. Following initial reports of potential heat protective properties in Astaxanthin supplemented rats, we present here results of a novel study...

Heatstroke (HS) is an acute, progressive life-threatening emergency. Animals, including military working dogs (IDFMWD), rapidly activate cytoprotective processes, e.g., heat shock proteins (HSPs) and antioxidative molecules, in response to heat stress. We hypothesized that serum HSPs (eHSP72) and oxidative stress markers would differ in IDFMWD with...

[This corrects the article DOI: 10.1371/journal.pone.0188551.].

Impact related traumatic brain injury (TBI) commonly influences high‐risk populations such as contact sports athletes and combat soldiers. Recovery results in mild to severe loss of motor and cognitive function. Prophylactic protection to enhance resilience and improve the rate and extent of recovery by nutrient supplementation is currently limited...

Introduction Exercise is considered a valuable nonpharmacological intervention modality in cardiac rehabilitation (CR) programs in patients with ischemic heart disease. The effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac patients' with reduced left ventricular functi...

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During the period of 1986–1997 the first 4 publications on the mechanical and metabolic properties of heat acclimated rat's heart were published. The outcome of these studies implied that heat acclimation, sedentary as well as combined with exercise training, confers long lasting protection against ischemic/reperfusion insult. These results promote...

Heatstroke results from a failure to dissipate accumulated heat during exposure to hot environments, or during strenuous physical exercise under heat stress. It is characterized by core body temperatures > 41º C, with central nervous system dysfunction. Functional morphology and thermoregulatory effectors differences between dogs and humans may req...

Background Moderate exercise training has been shown to decrease sudden cardiac death post myocardial infarction. However, the effects of intensive exercise are still controversial. Methods and Results Fourteen myocardial‐infarcted rats were divided into sedentary (n=8) and intensive training groups (n=6) and 18 sham control rats to sedentary (n=1...

Heatstroke is associated with systemic inflammatory response syndrome, leading to multiple organ dysfunction and death. Currently, there is no specific treatment decreasing hyperthermia-induced inflammatory/hemostatic derangements. Emerging studies indicate that histones leaking from damaged cells into the extracellular space are toxic, pro-inflamm...

Accumulating evidence suggests that the remodeling of mitochondrial function is important in heat acclimation (AC) and heat acclimation mediated cross‐tolerance (HACT). Cross‐tolerance is the phenomenon by which acclimation to one environmental stressor confers protection to novel stressors. In the ischemic AC heart, the protective role of the mito...

Studying 'Phenotypic plasticity' involves examination of phenotypic sensitivity to environmental factors by comparing the mean values of traits in multiple environments and aims to understand tolerance and survival in new settings. Reversible phenotypic changes that enable individuals to match their phenotype to environmental demands throughout lif...

Neuroprotection following prolonged exposure to high ambient temperatures (heat acclimation HA) develops via altered molecular programs such as cross-tolerance Heat Acclimation-Neuroprotection Cross-Tolerance (HANCT). The mechanisms underlying cross-tolerance depend on enhanced “on-demand” protective pathways evolving during acclimation. The protec...

Hypoxic interventions restore functions in human conditions, including COPD. Cardoso et al (The Faseb Journal,Suppl. April 2014,28,1,LB 787) have reported normalization of SpO2s when associating Exercise with @ Rest periods, while off supplemental O2, to the management of a 75 yrs old patient with stage IV COPD on LTOT. The use of Exercise while of...

During heat acclimation (AC) HIF‐1α is constitutively elevated in the heart and the brain. HIF‐1α plays a role in cardioprotection and in spontaneous recovery from traumatic brain injury in the AC phenotype via cross‐tolerance mechanisms (HACT). In this study, we aimed to elucidate whether constitutive vs. transient HIF‐1α up‐regulation is an essen...

This editorial focuses on articles submitted to the Temperature call “Thermal Physiology in a Changing Thermal World.” It highlights an array of topics related to thermoregulatory and metabolic functions in adverse environments, and the complexity and adaptability of the systems to changing climatic conditions, at various levels of body organizatio...

Faster re-induction of heat acclimation (AC) after its decline indicates "AC memory". Our previous results revealed involvement of epigenetic mechanisms of transcriptional regulation. We hypothesized that the decline of AC (DeAC) is a period of "dormant memory" during which many processes are alerted to enable rapid re-acclimation (ReAC). Using a g...

Angiotensin II receptor type 2 (AT2) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT2 activation following traumatic brain injury (TBI) in mice, a brain...

Long-term heat acclimation (34 °C, 30d) alters the physiological responses and the metabolic state of organisms. It also improves ability to cope with hypoxic stress via a cross-tolerance mechanism. Within the brain, the hippocampal and frontal cortex neurons are the most sensitive to hypoxia and cell death is mainly caused by calcium influx via gl...

Long-term exposure of mice to mild heat (34°C±1°C) confers neuroprotection against traumatic brain injury (TBI); however, the underling mechanisms are not fully understood. Heat acclimation (HA) increases hypothalamic angiotensin II receptor type 2 (AT2) expression and hypothalamic neurogenesis. Accumulating data suggest that activation of the brai...

Heat acclimation is a within‐life phenotypic adaptation to heat. Plasticity of the thermoregulatory system is crucial for the induction of heat acclimation. In the last two decades, it has become clear that heat causes adaptive shifts in gene expression which adjust the protein balance. These changes are part of the evolvement of the acclimated phe...

Preconditioning via heat acclimation (34°C 30 d) results in neuroprotection from traumatic brain injury due to constitutive as well as dynamic changes triggered by the trauma. Among these changes is Akt phosphorylation, which decreases apoptosis and induces HIF1α. In the present study we investigated the Akt downstream GSK3β/β -catenin pathway and...

During the past decade, our understanding of the cellular and molecular changes that occur after traumatic brain injury (TBI) has significantly increased, and the notion that endogenous neuroprotective cascades are also set in motion has been explored. One may speculate that the balance between the harmful and protective processes determines the fi...

The mechanisms whereby aerobic training reduces the occurrence of sudden cardiac death in humans are not clear. We test the hypothesis that exercise-induced increased resistance to ventricular tachycardia and fibrillation (VT/VF) involve an intrinsic remodeling in healthy hearts. Thirty rats were divided into a sedentary (CTRL, n = 16) and two exer...

Heart failure is of the most prevalent causes of death in the western world. Sea anemone contains a myriad of short peptide neurotoxins affecting many pharmacological targets, several of which possess cardiotonic activity. Here we describe the isolation and characterization of AdE-1, a novel cardiotonic peptide from the sea anemone Aiptasia diaphan...

Heat acclimation (HA), a well-established preconditioning model, confers neuroprotection in rodent models of traumatic brain injury (TBI). It increases neuroprotective factors, among them is hypoxia-inducible factor 1α (HIF-1α), which is important in the response to postinjury ischemia. However, little is known about the role of HIF-1α in TBI and i...

Long-term heat acclimation (LTHA; 30 days, 34°C) causes phenotypic adaptations that render protection against ischemic/reperfusion insult (I/R, 30 min global ischemia and 40 min reperfusion) via heat acclimation-mediated cross-tolerance (HACT) mechanisms. Short-term acclimation (STHA, 2 days, 34°C), in contrast, is characterized by cellular perturb...

Heat‐acclimation (AC) is a “within lifetime” phenotypicadaptation to long‐term elevations in ambient temperatures. Changes at all levels of body organization improve function in the heat. An inseparable benefit of AC is tolerance to novel stressors, via cross‐tolerance; the outcome of constitutive growth of cytoprotective molecule‐reserves, preclud...

This study is aimed to reveal essential gene/molecular pathways in heat acclimation (AC). Ceanorhabditis elegans wild type (N2) and HIF‐1 loss of function mutant (KO‐hif1) were used. The N2 worm, acclimated to heat at 25oC enhances survival when exposed to heat stress at the extreme temperature of 35oC. Concomitantly, the HIF‐1 loss of function mut...

Combined heat acclimation (AC) and exercise training (EX) enhance exercise performance in the heat while meeting thermoregulatory demands. We tested the hypothesis that different stress-specific adaptations evoked by each stressor individually trigger similar cardiac alterations, but when combined, overriding/trade-off interactions take place. We u...

The introduction of molecular biology to thermoregulation was delayed compared with its application in other research fields pertinent to human health and disease. Using principles from molecular biology, we revisited fundamental problems in integrative and environmental physiology and were able to explore new research horizons. Global genomic resp...

We have demonstrated that heat acclimation (AC) causes selective, long-lasting, transcriptional changes in cytoprotective and chromatin remodeling-associated genes, which maintain their AC transcriptome profile, despite the loss of the AC phenotype (Tetievsky et al. Physiol Genomics 34: 78-87, 2008). We postulated that AC memory involves upstream e...

Plasticity of the thermoregulatory system is a key factor for the induction of heat acclimation. Temperature-adaptive shifts in gene expression play an essential role in the processes involved. This review attempts to bridge the gap between the classical physiological heat acclimation profile and the molecular/cellular mechanisms underlying the evo...

Long-term heat acclimation (AC, 30d/34 degrees C) is a phenotypic adaptation leading to increased thermotolerance during heat stress (HS, 2 h 41 degrees C). AC also renders protection against ischemic/reperfusion (I/R, 30' global ischemia/40' reperfusion) insult via cross-tolerance mechanisms. In contrast to the protected AC phenotype, the onset of...

The renin-angiotensin system (RAS) plays a key role in heat acclimation, a process which induces adaptive changes in cardiac function. These changes are mediated in part by reduced thyroid hormone activity and improve myocardial function during and following exposure to various (non-heat) stresses such as ischemia. The aim of this study was to exam...

Heat acclimation (AC) is an evolutionarily conserved feature allowing adjustment to persistent changes in ambient temperature. The mechanisms underlying acclimation involve a continuum of physiologic changes, determined by temperature-adaptive shifts in gene expression. The AC heart generates greater pressure at lower O2 consumption, but at the exp...

Adaptation to heat (acclimation [ACC]) and exercise training (EX) require global changes at all levels of body organization to enhance muscle performance. In this investigation, we combined these stressors and examined physiological and genomic aspects of adaptation in skeletal muscle (soleus). Rats were divided into four groups: C (controls), ACC-...

Heat acclimation (HA) offers functional neuroprotection in mice after traumatic brain injury (TBI). This study further characterizes endogenous neuroprotection acquired by HA (34±1°C, 30 d) after TBI. We establish here the ability of HA to induce sustained functional benefits and to reduce activation of apoptotic pathways. Neurobehavioral recovery,...

Heat acclimation (AC) is an evolutionary conserved feature allowing organisms to adjust to prolonged/persistent changes in ambient temperature. An inseparable outcome of acclimation is the protection from novel stressors e.g. ischemia reperfusion (I/R) insult. In this study we evaluated the intrinsic apoptotic pathway and mitochondrial metabolic st...

Re‐induction of heat acclimation (AC) after its loss occurs markedly faster than in the initial AC session. We demonstrated that the underlying mechanisms involve continuous upregulation of cytoprotective and chromatin remodeler gene transcripts during deacclimation despite a return of the physiological AC phenotype to pre‐AC. Here we tested the hy...

Brain-derived neurotrophic factor (BDNF) conveys neuroprotection in various settings of experimental central nervous system injury. Using a model of endogenous neuroprotection, induced in mice by chronic exposure to moderate ambient heat (heat acclimation, HA), we have previously shown that neuroprotection following traumatic brain injury involves...

Sporadic findings in humans suggest that reinduction of heat acclimation (AC) after its loss occurs markedly faster than that during the initial AC session. Animal studies substantiated that the underlying acclimatory processes are molecular. Here we test the hypothesis that faster reinduction of AC (ReAC) implicates "molecular memory." In vivo mea...

Both heat acclimation (HA) and post-injury treatment with recombinant human erythropoietin (Epo, rhEpo, exogenous Epo) are neuroprotective against traumatic brain injury (TBI). Our previous data demonstrated that HA-induced neuroprotection includes improved functional recovery and reduced cerebral edema formation. Additionally, in earlier Western-b...

Long-term exposure to moderate ambient heat (heat acclimation, HA, 30 days at 34+/-1 degrees C) provides protection toward a variety of stressors including traumatic brain injury. As previous studies suggested an anti-inflammatory effect of HA and given the ability of augmented pre-injury anti-inflammatory cytokine expression to harbor neuroprotect...

Long-term heat exposure, known as heat acclimation (HA; 30 days at 34 +/- 1 degrees C) is neuroprotective against traumatic brain injury. Acclimated mice were previously found to display improved functional recovery as well as an increase in the levels of the specific erythropoietin receptor. As the activation of this receptor is known to facilitat...

Heat acclimation (AC) improves cardiac mechanical and metabolic performance. Using cardiomyocytes and isolated hearts from 30-day and 2-day acclimated rats (AC and AC-2d, 34 degrees C), we characterized cellular contractile mechanisms under normothermic (37 degrees C) and hyperthermic (39-42 degrees C) conditions. To determine contractile responses...

Heat acclimation (AC) is a "within lifetime" reversible phenotypic adaptation, enhancing thermotolerance and heat endurance via a transition to "efficient" cellular performance when acclimatory homeostasis is reached. An inseparable outcome of AC is the development of cross-tolerance (C-T) against novel stressors. This chapter focuses on central pl...

The fundamental functions of heat shock proteins (HSPs) are molecular chaperoning and cellular repair. There is little literature on the association between the numerous functions of HSPs and systemic integrative responses, particularly those controlled by the central nervous system. This chapter focuses on the role played by members of the HSP70 s...

Sub-lethal exposure to practically any harmful stimulus has been shown to induce consequent protection against more severe stress. This preconditioning (PC) effect may be achieved by exposure to different stressors, indicating that the induction of tolerance involves activation of common protective pathways. Chronic exposure to moderate heat (heat...

The induction of the heat-acclimated phenotype involves reprogramming the expression of genes encoding both constitutive and inducible proteins. In this investigation, we studied the global genomic response in the hypothalamus during heat acclimation, with and without combined hypohydration stress. Rats were acclimated for 2 days (STHA) or for 30 d...

During exertion in the heat, heat-intolerant (HI) subjects have a physiological disability in metabolic heat dissipation. The HI state is either permanent or temporary, depending on whether it stems from transient predisposing factors or inherent thermoregulatory dysfunction. In this investigation, we studied protein levels of heat shock protein (H...

The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-l-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by...

Experimental evidence indicates that long-term exposure to moderately high ambient temperature (heat acclimation, HA) mediates cross-tolerance to various types of subsequently applied stress. The transcriptional activator hypoxia-inducible factor 1 (HIF-1) has been implicated in playing a critical role in HA. It also regulates the expression of Ery...

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular hypoxic response. We previously showed that HIF-1 activation is essential for heat acclimation (AC) in Caenorhabditis elegans. Metabolic changes in AC rat hearts indicate HIF-1alpha activation in mammals as well. Here we characterize the HIF-1alpha profile and the transcriptional...

We studied the effect of heat acclimation on the neuromodulatory role of angiotensin (AngII) and nitric oxide during combined heat (39 degrees C) and hypohydration (water deprivation, -10% body weight) stress. Rats were divided into control (C), short (2d-STHA) or long (30d-LTHA) acclimation (34 degrees C) groups. AngII, 7-nitroindazole (7NI)-nNOS...

Acclimation to heat is a biphasic process involving a transient perturbed phase followed by a long lasting period during which acclimatory homeostasis is developed. In this investigation, we used cDNA stress microarray (Clontech Laboratory) to characterize the stress-related genomic response during the course of heat acclimation and to test the hyp...

Exposure to intense noise stress can cause a permanent noise-induced hearing loss which is thought to be due to elevation of reactive oxygen species in excess of the inherent antioxidant mechanisms of the cell. However, preconditioning to low levels of stress of one type can activate cellular mechanisms leading to the elevation of antioxidant level...

We investigated the central role of nitric oxide and AngII on thermoregulation in rats (Rattus norvegicus, Sabra strain,) undergoing heat-stress in euhydration or hypohydration (water deprivation, -10% b.wgt). Experimental rats received AngII (100 pm), 7-nitroindazole-an antagonist of neuronal nitric oxide synthase (7NI-100 nm), or AngII+7NI in a 5...

Heat acclimation produces concerted favorable adaptations in the mechanical and metabolic performance of the heart. Under normoxic condition this is displayed primarily by greater pressure generation with lower oxygen consumption. Altered expression of calcium regulatory proteins, EC coupling proteins and redistribution of the myosin isoenzyme to p...

Heat acclimation enhances cardiac efficiency by increasing stroke volume and decreasing heart rate. These adaptations involve biochemical changes in the contractile apparatus, switched on by altered expression of genes coding contractile and calcium-regulatory proteins and partially mediated by persistent low thyroxine. Heat acclimation also produc...

Chronic exposure to environmental heat improves tolerance via heat acclimation (AC). Our previous data on mammals indicate that reprogramming the expression of genes coding for stress proteins and energy-metabolism enzymes plays a major role. Knowledge of pathways leading to AC is limited. For their identification, we established a Caenorhabditis e...

The purpose of this investigation was to study the effect of thermal acclimation on the myocardium of rock pigeons. We determined the density and affinity of the b -adrenergic receptors in the left ventricle of cold-, heat-, and normothermic-acclimated pigeons by radioligand binding techniques. The mechanical performance of the left ventricle of th...

Based on our observations of energy sparing in heat-acclimated (AC) rat hearts, we investigated whether changes in preischemic glycogen level, glycolytic rate, and plasma thyroxine level mediate cardioprotection induced in these hearts during ischemia-reperfusion insults. Control (C) (24 degrees C), AC (34 degrees C, 30 days), acclimated-euthyroid...

Heat acclimation of rats has been shown to enhance endurance of rat hearts to ischemic insult and acute heat stress. Common protective features have been shown to be operative during both these stress-inducing conditions. To explore the role of membrane lipid composition in the adaptive response, we analyzed two major parameters that impact membran...

Heat acclimation upregulates 72-kDa heat shock protein (HSP72) and predisposes to faster activation of the heat shock response (HSR). This study investigates the role played by beta-adrenergic signaling and/or plasma thyroxine level in eliciting these features by using rats undergoing 1) heat acclimation (AC; 34 degrees C, 2 and 30 days); 2) AC wit...

Heat acclimation induces adaptive changes that improve the ability to cope with extreme environmental heat. Acclimatory homeostasis is manifested by an expanded dynamic thermoregulatory span (TRS), reflected in the intact organism by a lower temperature threshold (T(sh)) for heat dissipation, and delayed T(sh) for thermal injury. This principle sha...