Erythropoietin and the heart: facts and perspectives

EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio-renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases.     

Erythropoietin reduces the development of experimental inflammatory bowel disease

Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1) in the colon. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. Here we investigate the effects EPO has on the development of experimental colitis. To address this question, we used an experimental model of colitis induced by dinitrobenzene sulfonic acid (DNBS). When compared with DNBS-treated mice, EPO (1000 IU/kg day s.c.)-treated mice subjected to DNBS-induced colitis experienced significantly lower rates in the extent and severity of the histological signs of colon injury. DNBS-treated mice experienced diarrhea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) showed an intense staining in the inflamed colon. On the contrary, the treatment of DNBS-treated mice with EPO significantly reduced the degree of diarrhea and weight loss caused by administration of DNBS. EPO also caused a substantial reduction of the degree of colon injury, the rise in myeloperoxidase activity (mucosa), and the increase in staining (immunohistochemistry) for nitrotyrosine as well as the up-regulation of ICAM-1 caused by DNBS in the colon. Thus, treatment of rat with EPO reduces the degree of colitis caused by DNBS. We propose that EPO may be useful in the treatment of inflammatory bowel disease.     

A role for heme oxygenase-1 in the antioxidant and antiapoptotic effects of erythropoietin: the start of a good news/bad news story?

Erythropoietin (EPO) is the major regulator of erythropoiesis. EPO's actions have been shown to be antiapoptotic and dependent on JAK2 signaling and Akt phosphorylation. These effects serve as link between EPO and heme oxygenase-1 (HO-1). HO-1 is an inducible enzyme with potent antioxidant and antiapoptotic activities which are regulated by Akt signaling. EPO's ability to alter cellular systems that involve apoptosis and oxidants suggests that EPO treatments are likely to have multiple and different effects which may start a good news/bad news story. Recombinant human EPO is the recognized treatment of choice to address anemia and to stimulate erythropoiesis in chronic renal failure patients, through its antiapoptotic action which likely involves HO-1. On the other hand, EPO treatment to address anemia in cancer patients, while providing significant improvements in cancer patients' quality of life, its effects on survival are equivocal, likely due to its linkage with HO-1. Two clinical trials of EPO in patients with solid tumors have, in fact, shown specific negative effects on survival. However, EPO's effect on tumor growth and survival is not uniformily pro growth and pro survival, as EPO may act synergistically with chemotherapy to induce apoptosis. Finally, compounds have been synthesized that do not trigger EPO receptor and thus may allow experimental distinction and, therefore, at least potentially affect at the clinical level the tissue-protective effects of EPO (e.g., antiapoptosis) without provoking its other potentially detrimental effects.     

Mineralocorticoid receptor activation in myocardial infarction and failure: recent advances

Eur J Clin Invest 2012; 42 (10): 1112-1120 The classical view of aldosterone actions via the mineralocorticoid receptor (MR) limited to control of fluid balance and blood pressure homoeostasis has been progressively overcome by clinical and experimental evidence emphasizing the pleiotropic role of MR activation in the pathogenesis of cardiovascular disease. Clinical studies have shown the benefit of MR blockade in patients with left ventricular dysfunction and heart failure after myocardial infarction (MI), hypertension or diabetic nephropathy. Deleterious effects of MR activation include cardiac structural and electrical remodelling, cardiovascular fibrosis, inflammation and oxidative stress. Complexity of pathophysiological role of MR derives from the presence of circulating glucocorticoids at higher concentrations than aldosterone and the equal affinity of the MR for aldosterone, cortisol and corticosterone. Recent experimental studies using different animal models and genetic tools have deeply explored the cell-specific functional role of MR in cardiovascular pathology. This review addresses emerging preclinical studies as well as ongoing clinical trials regarding MR activation in MI and failure.     

Coagulation factor VII gene haplotypes, obesity-related traits, and cardiovascular risk in young women

BACKGROUND: Associations between common F7 haplotypes, plasma factor VII (FVII) levels, and cardiovascular risk have recently been reported in population studies involving predominantly European men. METHODS: We assessed associations between F7 haplotypes and cardiovascular risk in two US population-based studies: a case-control study of these alleles related to a decreased risk of arterial thrombotic outcomes such as myocardial infarction (MI) in young-to-middle-aged women (n = 671), and a cohort study of cardiovascular disease risk factors in young women (n = 1040). RESULTS: The high-expression F7 haplotype B (containing the promoter variant allele -402A) was associated with an increased FVII level among controls, but not with MI risk. Women carrying a> or =1 copy of the low FVII expression level haplotype C (containing the -401T/-323del/-122C and Gln353 alleles) had decreased FVII levels and decreased risk of MI (odds ratio 0.54, 95% CI 0.31-0.93) compared with women homozygous for the most common haplotype A. Haplotype C was also associated with a decreased body mass index (BMI) and an increased high-density lipoprotein (HDL) cholesterol level, but not with MI risk after adjustment for these metabolic risk factors. In a cohort study composed of young US women, individuals homozygous for haplotype C had a lower BMI and lower systolic blood pressure, but the association between the F7 haplotype and HDL cholesterol was not confirmed. CONCLUSION: Common FVII haplotypes may contribute to the risk of MI in women, but the mechanisms appear complex. The association between F7 haplotypes and MI susceptibility may be mediated in part through an influence on atherogenic risk factors such as BMI.     

Recombinant human erythropoietin prevents lipopolysaccharide-induced vascular hyporeactivity in the rat

Erythropoietin (EPO) is a hypoxia-inducible hormone that is essential for normal erythropoiesis in the bone marrow. Administration of recombinant human-EPO is currently being used for the therapy of anemia associated with chronic renal failure and cancer. Moreover, EPO reduces organ injury in experimental hemorrhagic as well as in splanchnic artery occlusion shock and preserves cardiac function after experimental cardiac I/R. Erythropoietin receptors are widely distributed in the cardiovascular system, including endothelial, smooth muscle, cardiac, and other cell types, and nonhematopoietic effects of EPO are increasingly recognized. Thus, the vasculature may be a biological target of EPO. Therefore, the aim of our study was to investigate whether EPO exerts a protective effect in septic shock by modulating vascular dysfunction and hyporeactivity. Rats received EPO (300 U/kg, i.v.) or vehicle 30 min before and 1 and 3 h after LPS (8 x 10 U/kg, i.v.). In vivo and ex vivo (aortic rings) experiments were performed to evaluate the vascular response to contracting and vasodilating agents. The expression of iNOS, intercellular adhesion molecule 1, poly(ADP)ribose polymerase, Bcl-xl, and Bcl-2 was evaluated by Western blot analysis in the rat aorta. We demonstrate that EPO significantly prevents LPS-induced vascular hyporeactivity and endothelial dysfunction. Interestingly, EPO inhibits the increase in iNOS, poly(ADP)ribose polymerase, and intercellular adhesion molecule 1 expression in the aorta of endotoxemic rats and attenuated the decline in the expression of both Bcl-xl and Bcl-2 caused by LPS. In conclusion, our data support the view that EPO has important nonerythropoietic effects protecting organ and tissue against injury and indicate that EPO may be useful in the therapy of patients with septic shock.     

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

IGF-1 (insulin-like growth factor-1) plays a unique role in the cell protection of multiple systems, where its fine-tuned signal transduction helps to preserve tissues from hypoxia, ischaemia and oxidative stress, thus mediating functional homoeostatic adjustments. In contrast, its deprivation results in apoptosis and dysfunction. Many prospective epidemiological surveys have associated low IGF-1 levels with late mortality, MI (myocardial infarction), HF (heart failure) and diabetes. Interventional studies suggest that IGF-1 has anti-atherogenic actions, owing to its multifaceted impact on cardiovascular risk factors and diseases. The metabolic ability of IGF-1 in coupling vasodilation with improved function plays a key role in these actions. The endothelial-protective, anti-platelet and anti-thrombotic activities of IGF-1 exert critical effects in preventing both vascular damage and mechanisms that lead to unstable coronary plaques and syndromes. The pro-survival and anti-inflammatory short-term properties of IGF-1 appear to reduce infarct size and improve LV (left ventricular) remodelling after MI. An immune-modulatory ability, which is able to suppress 'friendly fire' and autoreactivity, is a proposed important additional mechanism explaining the anti-thrombotic and anti-remodelling activities of IGF-1. The concern of cancer risk raised by long-term therapy with IGF-1, however, deserves further study. In the present review, we discuss the large body of published evidence and review data on rhIGF-1 (recombinant human IGF-1) administration in cardiovascular disease and diabetes, with a focus on dosage and safety issues. Perhaps the time has come for the regenerative properties of IGF-1 to be assessed as a new pharmacological tool in cardiovascular medicine.     

The need for wider and appropriate utilization of aspirin and statins in the treatment and prevention of cardiovascular disease

There is an increasing burden of occlusive cardiovascular disease (CVD) in developed, as well as in developing, countries. In fact, the WHO has projected that CVD will become the leading cause of death in the world in the next 10 years. The proximate cause of virtually all occlusive vascular events is thrombosis and the principal underlying cause is atherosclerosis. Aspirin, which inhibits platelet-dependent cyclooxygenase for the entire life of the platelet, has clinically important antithrombotic effects. Statins, which principally decrease low-density lipoprotein cholesterol, triglycerides and increase high-density lipoprotein cholesterol, have clinically important antiatherogenic effects. In secondary prevention, in a wide range of patients who have survived a prior myocardial infarction (MI), occlusive stroke, transient ischemic attack, as well as other high-risk conditions, long-term use of aspirin confers statistically significant and clinically important reductions in MI, stroke and CVD death. In addition, aspirin confers similar benefits when administered during acute MI or acute occlusive stroke. In primary prevention, aspirin confers a statistically significant and clinically important reduction in risk of a first MI but the data on stroke and CVD death remain inconclusive, so aspirin should be prescribed on an individual basis by the healthcare provider who weighs this clear benefit against long-term side effects. In a meta-analysis of 14 randomized trials of 90,056 subjects treated for 5 years, statins confer statistically significant and clinically important reductions in MI, stroke, CVD death and total mortality. In a meta-analysis of randomized trials of statins, in which aspirin was used in varying frequencies, the combination of aspirin and statins conferred greater clinical benefits than either agent alone on MI, occlusive stroke and CVD death. At present, the wider and more appropriate use of aspirin and statins will reduce premature MI, stroke and CVD death.     

Circulating activated protein C is reduced in young survivors of myocardial infarction and inversely correlates with the severity of coronary lesions.

BACKGROUND: Cardiovascular risk factors for myocardial infarction (MI) are less frequent in younger than in older MI survivors. Therefore, the thrombotic component of MI may play a more important role at a young age. As activated protein C (APC) provides systemic anticoagulant and anti-inflammatory protection, a low plasma APC level may be an arterial thrombotic risk factor. AIM: To determine whether there is an association between reduced APC levels and early MI and severe coronary lesions. METHODS: APC was measured in 231 young MI survivors and 231 controls. RESULTS: Low APC levels were significantly associated with MI. Compared with the fourth quartile, the odds ratio (OR) for APC values in the first quartile was 3.7 [95% confidence interval (CI) = 2.1-6.4], and 3.2 (1.5-7.0) after adjustment for cardiovascular risk factors. Moreover, each decrease of 0.43 ng mL(-1) (1 SD) in APC increased the OR 1.7 times (1.4-2.2), and 1.5 times (1.2-1.9) after adjustment for cardiovascular risk factors. Low APC levels were also associated with the number of coronary arteries affected and with the severity of coronary lesions (P < 0.001). CONCLUSIONS: There is a significant association between low circulating APC levels and both early MI and the extent and severity of coronary atherosclerosis, which might be related to the anticoagulant and anti-inflammatory properties of APC.     

Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

PurposeSystemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension.MethodsPubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed.FindingsThe potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in adulthood. In addition, increasing evidence suggests that estrogen may have distinct temporal effects on cardiovascular risk factors during SLE.ImplicationsData from experimental models of lupus suggest that estrogens may have an important permissive role for developing SLE early in life. However, their role in adulthood remains unclear, particularly for the effect on cardiovascular disease and its risk factors. Additional work is needed to understand the effect of estrogens in human SLE, and preclinical studies in experimental models of SLE may contribute important mechanistic insight to further advance the field.     

Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target

Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR-/- rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.     

From pathophysiology to targeted therapy for atherothrombosis: a role for the combination of statin and aspirin in secondary prevention

Atherothrombosis results from direct interaction between the atherosclerotic plaque and arterial thrombosis, and underlies most forms of cardiovascular disease (CVD). The pathophysiology of atherosclerosis is now recognised to involve endothelial dysfunction and dyslipidemia with cholesterol accumulation, as well as critical immuno-inflammatory and apoptotic dimensions. Erosion or rupture of a vulnerable, lipid-rich, inflammatory atherosclerotic plaque triggers the formation of a platelet-rich thrombus that may partially or completely occlude the artery, with resultant clinical scenarios including stable and unstable angina, acute myocardial infarction (MI) and ischaemic stroke. Insight into the pathophysiology of atherothrombosis indicates that an integrated risk factor approach, focusing particularly on management of dyslipidaemia (with a statin) and thrombosis (with aspirin), may constitute an optimal therapeutic approach. Both agents have established roles in secondary prevention. Statin action on atherogenic lipoproteins mediates plaque stabilisation, modification of plaque morphology and attenuation of inflammation, and may lead to plaque regression, while aspirin reduces platelet activation and aggregation, decreases release of inflammatory cytokines at sites of vascular injury and attenuates vasoconstriction. Given these complementary modes of action, this combination would be a logical choice for reducing atherothrombotic risk in patients with CVD. Meta-analysis of 5 major clinical studies has demonstrated that the combination of pravastatin plus aspirin was significantly more effective than either agent alone in reducing the relative risk of key cardiovascular endpoints including MI and ischaemic stroke. This combination may therefore represent an important, cost-efficient therapeutic approach to reduction of cardiovascular risk and prevention of recurrent events in stable CVD.     

Lack of association between cystatin C and different coronary atherosclerotic manifestations

Cystatin C (CysC) is known to be related to cardiovascular disease (CVD), including the presence and severity of coronary artery disease (CAD) and future clinical events. In this study, the association between CysC levels and (1) coronary artery calcification (CAC) in asymptomatic individuals from the general population as well as (2) different subgroups of patients with suspected or definite acute myocardial infarction (MI) was investigated. CysC levels were measured in serum from asymptomatic individuals as part of a screening study for CAC using non-contrast cardiac CT scan (N?=?1039) as well as in subgroups of hospitalized patients with a suspected MI (N?=?769). CysC was not associated with CAC in asymptomatic individuals after adjusting for relevant risk factors. No difference in CysC levels was observed between patients with type 1?MI (1.07?mg/L) and patients with normal troponin (with or without prior CAD: 1.14 and 1.01?mg/L, respectively). However, patients with type 2?MI and patient subgroups with elevated troponin but without MI had significantly higher CysC levels (1.24, 1.23 and 1.31?mg/L), even after adjusting for other risk factors. CysC was not associated with CAC in middle-aged asymptomatic individuals from the general population. Furthermore, CysC levels were found to be significantly lower in patients with type 1?MI compared to patients with type 2?MI and patients with elevated troponins but without MI. Thus, in two independent and clinically different populations, no association between CysC and coronary atherosclerotic manifestations could be demonstrated.     

Mapping the involvement of BA 4a and 4p during Motor Imagery

Motor Imagery (MI) is an attractive but intriguing means to access the motor network. There are marked inconsistencies in the functional imaging literature regarding the degree, extent and distribution of the primary motor cortex (BA 4) involvement during MI as compared to Executed Movement (EM), which may in part be related to the diverse role of BA 4 and its two subdivisions (i.e., 4a and 4p) in motor processes as well as to methodological issues. Here we used fMRI with monitoring of compliance to show that in healthy volunteers optimally screened for their ability to perform MI the contralateral BA 4 is involved during MI of a finger opposition sequence (2, 3, 4, 5; paced at 1 Hz), albeit less than during EM of the same sequence, and in a location sparing the hand area. Furthermore, both 4a and 4p subdivisions were found to be involved in MI, but the relative involvement of BA 4p appeared more robust and closer to that seen with EM. We suggest that during MI the role of BA 4 and its subdivisions may be non-executive, perhaps related to spatial encoding, though clearly further studies are needed. Finally, we report a similar hemispheric activation balance within BA 4 with both tasks, which extends the commonalities between EM and MI.     

Serum resistin as a novel marker of erythropoietin resistance in nondiabetic patients on hemodialysis

The use of higher erythropoietin (EPO) doses is associated with an increased risk of an adverse outcome and increased mortality in patients with renal failure. Resistin is related to heart disease, and may contribute to an increased atherosclerotic risk. We hypothesized that a link between resistin and EPO responsiveness may exist. We therefore investigated the relationship between resistin and the EPO resistance index (ERI) in nondiabetic hemodialysis (HD) patients. Fifty-seven patients enrolled in the study underwent HD for ≥ 3 months and intravenous EPO therapy to maintain a target hemoglobin (Hb) level of 11.0 g/dl. The ERI was defined as the weekly EPO dose per unit Hb per body weight. The mean patient age was 52.6 ± 11.9 years and the mean time on dialysis was 4.9 ± 4.4 years. Serum Hb and ERI were 10.4 ± 0.7 g/dl, and 13.3 ± 7.0 (IU/kg/week/g/dl), respectively. Serum resistin levels were 23.6 ± 9.3 μg/L. EPO resistance is associated with low body mass index (BMI) (coefficient β =-0.393, p = 0.002) and with high serum resistin levels (coefficient β = 0.332, p = 0.018). According to a multiple regression analysis, the serum resistin level was a significant independent factor related to EPO resistance (p = 0.017). The results suggest that serum resistin levels reflect EPO responsiveness in nondiabetic HD patients. Resistin may therefore be considered as a new marker of EPO responsiveness in HD patients.     

Possible association of acute lateral-wall myocardial infarction and bitter orange supplement

OBJECTIVE: To report a possible incidence of acute lateral-wall myocardial infarction (MI) coinciding with the use of a Citrus aurantium L. (bitter orange)-containing dietary supplement in a patient with undetected coronary vascular disease. CASE SUMMARY: A 55-year-old white woman presented to the emergency department with symptoms of dull aching shoulder and chest pain. A review of medications during cardiac rehabilitation revealed the patient had ingested a multicomponent dietary supplement for weight loss containing 300 mg of bitter orange (Edita's Skinny Pill) for the past year. Although the patient's past medical history did not include hypertension, coronary disease, or hyperlipidemia, an arteriogram revealed a lesion in the left main coronary artery. She did have a smoking history. She was diagnosed with acute lateral-wall MI and hospitalized for 4 days. DISCUSSION: Consumers generally consider dietary supplements safe. However, some supplements taken for weight loss contain ingredients that have been associated with cardiovascular events. Although consumers are becoming more aware of the serious adverse effects secondary to products containing ingredients such as Ma huang and ephedra, reports involving other ingredients are increasing. Bitter orange or synephrine, found in bitter orange, has been associated with adverse cardiovascular reactions. Based on the Naranjo probability scale, C. aurantium is possibly associated with this cardiovascular event. CONCLUSIONS: The use of C. aurantium-containing supplements may present as a risk for cardiovascular toxicity; however, additional studies/case reports are needed to validate this conclusion.     

Protective effect of recombinant human erythropoietin in type II Gaucher disease patient cells by scavenging endoplasmic reticulum stress

Gaucher disease (GD) is an inherited disorder characterized by excessive accumulation of glucocerebroside in cells due to a non-functional glucocerebrosidase that is linked to programmed cell death pathways. Although clinical manifestations vary, type II GD is the most severe phenotype characterized by endoplasmic reticulum (ER) stress, neurological dysfunction, and anemia. Recombinant human erythropoietin (EPO) has been very popular for treating renal anemia and recently was shown to have extra-hematopoietic effects including neuroprotective properties. EPO's hematopoietic and neuroprotective effects prompted us to test EPO's beneficial action on type II GD patient cells. Initially, to examine the responsiveness of type II GD cells to EPO, the expression of the EPO receptor was determined at mRNA and protein levels. EPO effects on signaling pathways and ER stress in GD cells were also investigated. Finally, the proliferative effect of EPO on GD cells was verified. We found that EPO stimulated signaling pathways, enhanced the expression of glucocerebrosidase, reduced ER stress marker protein levels, and enhanced the proliferation rate of type II GD patient cells. This novel approach involving a beneficial role of EPO in GD should provide insights into new concepts for treating GD.     

Relationship between erythropoietin and nitric oxide in the contraction of rat renal arcuate arteries and human umbilical vein endothelial cells.

We have investigated the effects of recombinant human erythropoietin (EPO) on the responses of rat renal arcuate arteries to dopamine, noradrenaline and acetylcholine and on the release of NO from human umbilical vein endothelial cells (HUVEC) in culture. Noradrenaline induced a concentration-dependent constriction and acetylcholine a concentration-dependent relaxation of the vessels. The effects of dopamine were concentration-dependent, leading to relaxation of the vessels at low concentrations and contraction of the vessels at high concentrations. N(G)-Nitro-L-arginine methyl ester (L-NAME; 0.1 mM) did not change the vasoconstrictor responses to noradrenaline and dopamine, but inhibited the acetylcholine- and dopamine-induced vasorelaxation. Neither 0.1 nor 20 units.ml(-1) EPO affected noradrenaline-induced constriction, or dopamine- or acetylcholine-induced relaxation, of the vessels. EPO at 20 units. ml(-1) attenuated dopamine-induced constriction of the vessels. This effect was blunted by application of L-NAME, suggesting that EPO may stimulate dopamine-mediated NO release from these vessels. EPO stimulated NO release from the resting HUVEC in a concentration- and time-dependent manner, an effect that was inhibited by the presence of N(G)-nitro-L-arginine. These data suggest that, in vitro, EPO is able to stimulate NO release from rat renal arcuate arteries and HUVEC in culture. Whether these acute short-term actions can be related to the longer-term actions of EPO remains to be resolved.     

Effects of Combination of Proliferative Agents and Erythropoietin on Left Ventricular Remodeling Post–Myocardial Infarction

Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic gonadotrophin (hCG) would improve post–myocardial infarction (MI) effects synergistically. Methods: After MI, five to seven animals were randomly assigned to each of the following treatments: control; hCG; EPO; hCG + EPO, and prolactin (PRL) + EPO. Follow‐up echocardiograms were performed to assess cardiac structure and function. Apoptosis was determined by terminal deoxynucleotidyl transferase‐mediated dUTP nick end‐labeling (TUNEL) assay and western blot analysis for apoptosis‐related proteins, and cell proliferation by immunostaining for Ki67 and c‐kit cells. Results: The MI‐mediated increased chamber systolic dimension (p < 0.05 in controls) was attenuated by hCG, EPO, and hCG + EPO (p < 0.05 vs. control) but not PRL + EPO. Similarly all treatment groups, except PRL + EPO, reduced MI‐induced increases (p < 0.05 vs. control) in ejection fraction (EF). The functional improvement in the EPO‐treated groups was accompanied by increased capillary density. Apoptosis was markedly reduced in all treated groups. Significantly more cardiac c‐kit⁺ cells were found in the hCG + EPO group. Conclusion: Our findings revealed that EPO, hCG, or their combination ameliorate cardiac remodeling post‐MI. Whereas EPO stimulates neovascularization only and hCG + EPO stimulates c‐kit+ cell proliferation. These data suggest that combining mobilizing and proliferative agents adds to the durability and sustainability of cytokine‐based therapies for remodeling post‐MI. Clin Trans Sci 2011; Volume 4: 168–174     

Selected topics related to occupational exposures. Part V. Occupational cardiovascular disease

Cardiovascular disease is common in the United States. Several occupational exposures, such as carbon disulfide and organic nitrates, are believed to cause occupational cardiovascular disease. In addition some other agents, such as lead and cadmium, may indirectly cause cardiovascular disease through their effects on blood pressure. For other agents (ie, carbon monoxide, solvents, and chlorofluorocarbons), acute exposure and high levels may cause cardiovascular disease but may not cause cardiovascular disease through long-term or low levels. A primary care physician who has a patient with a new or unstable cardiovascular disease should obtain an occupational history to assess whether occupational exposures may be playing a role. An occupational history may indicate potential cardiovascular risks. Such risks can include exposure to certain chemicals and metals, physical factors, exertion, or psychological stress. The primary care physician should be able to assess the situation and advise the patient, as well as the employer, about restrictions or accommodations that may need to be made.