Fawzi A. Babiker

Estrogenic hormone action in the heart: regulatory network and function.

Cardiovascular diseases are the leading cause of death in the industrialised countries and display significant gender-based differences. Estrogen plays an important role in the pathogenesis of heart disease and is able to modulate the progression of cardiovascular disease. The focus on the beneficial influence of estrogen is gradually shifting from the vascular system to the myocardium. The presence of functional estrogen receptors in the myocardium has been demonstrated. Estrogen is important for cardiovascular baseline physiology and modulates the myocardial response under pathological conditions. Here we summarise the current knowledge of the regulatory network of estrogenic action in the myocardium and its effects on cardiovascular function.

17β-Estradiol Antagonizes Cardiomyocyte Hypertrophy by Autocrine/Paracrine Stimulation of a Guanylyl Cyclase A Receptor-Cyclic Guanosine Monophosphate-Dependent Protein Kinase Pathway

Background—Significant gender-related differences exist in the development of left ventricular hypertrophy (LVH). In addition, administration of 17&bgr;-estradiol (E2) to ovariectomized female mice attenuates the development of LVH, demonstrating an antagonistic role for E2 in this process, although no molecular mechanism has been proposed for this phenomenon. Methods and Results—E2 attenuated phenylephrine and endothelin-1 induced hypertrophy in neonatal cardiomyocytes, and E2 directly induced atrial natriuretic factor (ANF) expression as assessed by Northern blot, immunocytochemical analyses, and transient transfection assays using ANF promoter deletion fragments. Both the antihypertrophic effects and ANF induction could be blocked by the estrogen receptor antagonist ICI 182,780, which demonstrates a genomic, estrogen receptor-dependent pathway. To mimic E2-induced autocrine/paracrine effects through stimulation of the guanylyl cyclase A receptor (ANF receptor), cardiomyocytes were stimulated with phenylephrine or endothelin-1 in the presence of exogenous ANF or 8-bromo-cyclic guanosine monophosphate (cGMP), both of which attenuated agonist-induced hypertrophy. Both estrogen and ANF increased cGMP activity. The antihypertrophic effect of ANF could be reduced with extracellular ANF antibodies in a dose-dependent manner. cGMP-dependent protein kinase mediates the antihypertrophic effects of E2, so cardiomyocytes were agonist stimulated in the presence of the cGMP-dependent protein kinase blocker KT-5823. KT-5823 not only reversed the antihypertrophic properties of E2, ANF, or 8-bromo-cGMP, but also evoked potentiation of hypertrophy. Conclusions—E2-mediated induction of ANF in cardiac hypertrophy contributes to its antagonistic effects in LVH.

Estrogen Receptor β Protects the Murine Heart Against Left Ventricular Hypertrophy

Background—Left ventricular hypertrophy (LVH) displays significant gender-based differences. 17&bgr;-estradiol (E2) plays an important role in this process because it can attenuate pressure overload hypertrophy via 2 distinct estrogen receptors (ERs): ER&agr; and ER&bgr;. However, which ER is critically involved in the modulation of LVH is poorly understood. We therefore used ER&agr;-deficient (ER&agr;−/−) and ER&bgr;-deficient (ER&bgr;−/−) mice to analyze the respective ER-mediated effects. Methods and Results—Respective ER-deficient female mice were ovariectomized and were given E2 or placebo subcutaneously using 60-day release pellets. After 2 weeks, they underwent transverse aortic constriction (TAC) or sham operation. In ER&agr;−/− animals, TAC led to a significant increase in ventricular mass compared with sham operation. E2 treatment reduced TAC induced cardiac hypertrophy significantly in wild-type (WT) and ER&agr;−/− mice but not in ER&bgr;−/− mice. Biochemical analysis showed that E2 blocked the increased phosphorylation of p38–mitogen-activated protein kinase observed in TAC-treated ER&agr;−/− mice. Moreover, E2 led to an increase of ventricular atrial natriuretic factor expression in WT and ER&agr;−/− mice. Conclusions—These findings demonstrate that E2, through ER&bgr;-mediated mechanisms, protects the murine heart against LVH.

Oestrogen modulates cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms.

Aim:  Observational and clinical studies suggest different responses upon sex hormone replacement therapy in ischaemic heart disease. Few studies, however, have examined the impact of oestrogen receptor‐dependent mechanisms on the extent of injury after myocardial infarction (MI). Therefore, we set out to evaluate the effect of oestrogen (E2) replacement on infarct size and remodelling, and the respective role of the oestrogen receptors (ER)α and ‐β in this process, using ERα‐ and ERβ‐deficient mice.

Re-expression of alpha skeletal actin as a marker for dedifferentiation in cardiac pathologies.

Differentiation of foetal cardiomyocytes is accompanied by sequential actin isoform expression, i.e. down‐regulation of the ‘embryonic’ alpha smooth muscle actin, followed by an up‐regulation of alpha skeletal actin (αSKA) and a final predominant expression of alpha cardiac actin (αCA). Our objective was to detect whether re‐expression of αSKA occurred during cardiomyocyte dedifferentiation, a phenomenon that has been observed in different pathologies characterized by myocardial dysfunction. Immunohistochemistry of αCA, αSKA and cardiotin was performed on left ventricle biopsies from human patients after coronary bypass surgery. Furthermore, actin isoform expression was investigated in left ventricle samples of rabbit hearts suffering from pressure‐ and volume‐overload and in adult rabbit ventricular cardiomyocytes during dedifferentiation in vitro. Atrial goat samples up to 16 weeks of sustained atrial fibrillation (AF) were studied ultrastructurally and were immunostained for αCA and αSKA. Up‐regulation of αSKA was observed in human ventricular cardiomyocytes showing down‐regulation of αCA and cardiotin. A patchy re‐expression pattern of αSKA was observed in rabbit left ventricular tissue subjected to pressure‐ and volume‐overload. Dedifferentiating cardiomyocytes in vitro revealed a degradation of the contractile apparatus and local re‐expression of αSKA. Comparable αSKA staining patterns were found in several areas of atrial goat tissue during 16 weeks of AF together with a progressive glycogen accumulation at the same time intervals. The expression of αSKA in adult dedifferentiating cardiomyocytes, in combination with PAS‐positive glycogen and decreased cardiotin expression, offers an additional tool in the evaluation of myocardial dysfunction and indicates major changes in the contractile properties of these cells.

Awareness of hypertension and factors associated with uncontrolled hypertension in Sudanese adults : cardiovascular topic

Background The incidence of hypertension (HTN) has increased rapidly in the Sudan in the last few years. The aim of this study was to determine the prevalence of uncontrolled HTN and the risk factors associated with it in Sudanese adults. Methods This study was cross sectional. Data were collected using structured questionnaires filled in during interviews with subjects visiting referral clinics in Khartoum, the capital city of Sudan. Blood pressure (BP) was measured using a digital sphygmomanometer. A digital balance was used for determination of body weight and a traditional cloth tape measure was used for measuring height, for calculation of body mass index. Results This study included 200 subjects, 46% male and 54% female. In the whole study, 82% of subjects (p < 0.001) were on hypertension drug treatment. Of these, 64% had their BP controlled to normal standards set by the World Health Organistion (< 140/90 mmHg). The prevalence of uncontrolled BP was significantly (p < 0.001) higher in males (61%) compared to females (15%). When the risk factors of HTN were considered, 54% of the subjects had a positive family history of HTN and 52% were smokers. Uncontrolled BP was found to be significantly (p < 0.001) higher in smoking males (43%) compared to females (4%). It was also high in people with higher education (55%) and workers (41%). In these groups, when genders were considered separately, uncontrolled hypertension was significantly (p < 0.01) higher in males than females with higher education (67 and 40%, respectively), and in workers (86 and 10%, respectively). Uncontrolled HTN was associated with overweight and obesity in 45 and 29% of the subjects, respectively. Most of the interviewed subjects were not aware of the consequences of HTN and its associated risk factors. Conclusions Uncontrolled HTN was associated with risk factors of HTN and lifestyle, and was more prominent in the male gender. The ignorance of the interviewed subjects about HTN, its associated risk factors, changes in lifestyle and adherence to taking the medication may have been a major factor in the prevalence of uncontrolled HTN.

Endogenous angiotensin-(1-7)/Mas receptor/NO pathway mediates the cardioprotective effects of pacing postconditioning.

The aim of the present study was to investigate the role of the ANG-(1-7) receptor (Mas) and nitric oxide (NO) in pacing postconditiong (PPC)-mediated cardioprotection against ischemia-reperfusion injury. Cardiac contractility and hemodynamics were assessed using a modified Langendorff system, cardiac damage was assessed by measuring infarct size and creatinine kinase levels, and levels of phosphorylated and total endothelial NO synthase (eNOS) were determined by Western blot analysis. Isolated hearts were subjected to 30 min of regional ischemia, produced by fixed position ligation of the left anterior descending coronary artery, followed by 30 min of reperfusion (n = 6). Hearts were also subjected to PPC (three cycles of 30 s of left ventricular pacing alternated with 30 s of right atrial pacing) and/or treated during reperfusion with ANG-(1-7), N(G)-nitro-l-arginine methyl ester, or the Mas antagonist (d-Ala7)-ANG I/II (1-7). The PPC-mediated improvement in cardiac contractility and hemodyanamics, cardiac damage, and eNOS phosphorylation were significantly attenuated upon treatment with (d-Ala7)-ANG I/II (1-7) or N(G)-nitro-l-arginine methyl ester. Treatment with ANG-(1-7) improved cardiac function and reduced infarct size and creatinine kinase levels; however, the effects of ANG-(1-7) were not additive with PPC. In conclusion, these data provide novel insights into the cardioprotective mechanisms of PPC in that they involve the Mas receptor and eNOS and further suggest a potential therapeutic role for ANG-(1-7) in cardiac ischemic injury.

Pacing Postconditioning: Recent Insights of Mechanism of Action and Probable Future Clinical Application.

Ischemic heart disease, also known as coronary heart disease or coronary artery disease, accounts for >50% of cardiovascular events and is a leading cause worldwide of morbidity and mortality. Hypoperfusion of the heart is the major cause of injury in ischemic heart disease, as it results in the death of cardiomyoctes due to a lack of oxygen and energy. This injury ultimately leads to a dead area in the heart called infarcted area or myocardial infarction. The formation of myocardial infarction leads to a lengthy process of remodeling which causes many changes in the architecture and the electrophysiology of the heart. These changes may eventually lead to death due to arrhythmia or heart failure. Tremendous efforts have been made over the last decades to decrease the burden of ischemic reperfusion (I/R) injury. The first salvage to the ischemic heart is reperfusion; however, this procedure is associated with a subsequent reperfusion injury. In the 1980s, a method known as preconditioning was introduced and showed great potential in combating ischemic heart disease, but this technique is limited by the difficulty of its translation to the clinic as it requires the anticipation of an occurrence of ischemic heart disease. Not long after, a new method, postconditioning, was introduced. This method showed great success, and several studies were performed to investigate its signaling cascades and the possibility of its translation to the clinic. Thereafter, several trials were made, and many methods of postconditioning were developed. One of these is intermittent dyssynchrony, pacing postconditioning (PPC), of the heart, which involves brief episodes of electrical pacing. PPC afforded a pronounced protection to the heart against I/R injury, similar to that afforded by pre- and postconditioning.

The Interplay between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

Background Accumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC) maneuvers in animal models and more recently in humans. The procedure however remains to be optimized and its interaction with physiological systems remains to be further explored. The renin angiotensin system (RAS) plays a dual role in ischemia/reperfusion (I/R) injury. The interaction between RAS and PPC induced cardiac protection is however not clearly understood. We have recently demonstrated that angiotensin (1–7) via Mas receptor played a significant role in PPC mediated cardiac protection against I/R injury. Objective The objective of this study was to investigate the role of angiotensin converting enzyme (ACE)—chymase—angiotensin II (Ang II)—angiotensin receptor 1 (AT1) axes of RAS in PPC mediated cardiac protection. Methods Isolated rat hearts were subjected to I/R (control) or PPC in the presence or absence of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) or AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined histologically using TTC staining and biochemically by measuring creatine kinase (CK) and lactate dehydrogenase levels. Results Cardiac hemodynamics were significantly (P<0.001) improved and infarct size and cardiac enzymes were significantly (P<0.001) reduced in hearts subjected to PPC relative to hearts subjected to I/R injury. Exogenous administration of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesized Ang II protected against I/R induced cardiac damage yet did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection in isolated rat hearts. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt components of the reperfusion injury salvage kinase (RISK) pathway. Conclusions This study demonstrate a novel role of endogenously produced Ang II in mediating I/R injury and highlights the significance of AT1 signaling in PPC mediated cardiac protection in isolated rodents hearts ex vivo. The interaction between Ang II-AT1 and PPC appears to involve alterations in the activation state of ERK1/2 and Akt components of the RISK pathway.

Lead exposure induces oxidative stress, apoptosis, and attenuates protection of cardiac myocytes against ischemia–reperfusion injury

Abstract Disrupting role of lead toxicity in heart functions and prognosis of cardiovascular diseases is not well known. This study investigated the interference of lead in heart functions and pacing postconditioning-mediated protection to the heart from ischemia–reperfusion injury. Lead exposure decreased the body weight and increased the heart weight in male rats (p < 0.001). Long-term lead exposure (45 days exposure to lead) increased total oxidant levels (p < 0.001) in the heart. Furthermore, lead exposure abrogated the pacing postconditioning-mediated protection from ischemia–reperfusion injury. The latter effect showed an association with reduced total antioxidants levels (p < 0.001). In the short-term study (5 days exposure to lead), pacing postconditioning protected the heart from ischemia–reperfusion injury despite the reduced total antioxidant levels (p < 0.001). Lead toxicity caused a drastic increase in the heart weight in male rats and apoptosis. The induced oxidative stress showed association with the lack of pacing postconditioning-mediated protection of the heart. However, long-term lead exposure eliminated pacing postconditioning-mediated protection of the heart from ischemia–reperfusion injury.