Adaptive and maladaptive roles of different angiotensin receptors in the development of cardiac hypertrophy and heart failure.

Angiotensin II (Ang II) is formed by the action of angiotensin-converting enzyme (ACE) in the renin-angiotensin system. This hormone is known to induce cardiac hypertrophy and heart failure and its actions are mediated by the interaction of both pro- and antihypertrophic Ang II receptors (AT1R and AT2R). Ang II is also metabolized by ACE 2 to Ang-(1-7), which elicits the activation of Mas receptors (MasR) for inducing antihypertrophic actions. Since heart failure under different pathophysiological situations is preceded by adaptive and maladaptive cardiac hypertrophy, we have reviewed the existing literature to gain some information regarding the roles of AT1R, AT2R, and MasR in both acute and chronic conditions of cardiac hypertrophy. It appears that the activation of AT1R may be involved in the development of adaptive and maladaptive cardiac hypertrophy as well as subsequent heart failure because both ACE inhibitors and AT1R antagonists exert beneficial effects. On the other hand, the activation of both AT2R and MasR may prevent the occurrence of maladaptive cardiac hypertrophy and delay the progression of heart failure, and thus therapy with different activators of these antihypertrophic receptors under chronic pathological stages may prove beneficial. Accordingly, it is suggested that a great deal of effort should be made to develop appropriate activators of both AT2R and MasR for the treatment of heart failure subjects.

The Role of Pro-Inflammatory Cytokines in the Pathogenesis of Cardiovascular Disease.

With cardiovascular disease (CVD) being a primary source of global morbidity and mortality, it is crucial that we understand the molecular pathophysiological mechanisms at play. Recently, numerous pro-inflammatory cytokines have been linked to several different CVDs, which are now often considered an adversely pro-inflammatory state. These cytokines most notably include interleukin-6 (IL-6),tumor necrosis factor (TNF)α, and the interleukin-1 (IL-1) family, amongst others. Not only does inflammation have intricate and complex interactions with pathophysiological processes such as oxidative stress and calcium mishandling, but it also plays a role in the balance between tissue repair and destruction. In this regard, pre-clinical and clinical evidence has clearly demonstrated the involvement and dynamic nature of pro-inflammatory cytokines in many heart conditions; however, the clinical utility of the findings so far remains unclear. Whether these cytokines can serve as markers or risk predictors of disease states or act as potential therapeutic targets, further extensive research is needed to fully understand the complex network of interactions that these molecules encompass in the context of heart disease. This review will highlight the significant advances in our understanding of the contributions of pro-inflammatory cytokines in CVDs, including ischemic heart disease (atherosclerosis, thrombosis, acute myocardial infarction, and ischemia-reperfusion injury), cardiac remodeling (hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac apoptosis, and heart failure), different cardiomyopathies as well as ventricular arrhythmias and atrial fibrillation. In addition, this article is focused on discussing the shortcomings in both pathological and therapeutic aspects of pro-inflammatory cytokines in CVD that still need to be addressed by future studies.

The Efficacy of Vitamins in the Prevention and Treatment of Cardiovascular Disease.

Vitamins are known to affect the regulation of several biochemical and metabolic pathways that influence cellular function. Adequate amounts of both hydrophilic and lipophilic vitamins are required for maintaining normal cardiac and vascular function, but their deficiencies can contribute to cardiovascular abnormalities. In this regard, a deficiency in the lipophilic vitamins, such as vitamins A, D, and E, as well as in the hydrophilic vitamins, such as vitamin C and B, has been associated with suboptimal cardiovascular function, whereas additional intakes have been suggested to reduce the risk of atherosclerosis, hypertension, ischemic heart disease, arrhythmias, and heart failure. Here, we have attempted to describe the association between low vitamin status and cardiovascular disease, and to offer a discussion on the efficacy of vitamins. While there are inconsistencies in the impact of a deficiency in vitamins on the development of cardiovascular disease and the benefits associated with supplementation, this review proposes that specific vitamins may contribute to the prevention of cardiovascular disease in individuals at risk rather than serve as an adjunct therapy.

Role of Na+-K+ ATPase Alterations in the Development of Heart Failure.

Na+-K+ ATPase is an integral component of cardiac sarcolemma and consists of three major subunits, namely the α-subunit with three isoforms (α1, α2, and α3), ß-subunit with two isoforms (ß1 and ß2) and γ-subunit (phospholemman). This enzyme has been demonstrated to transport three Na and two K ions to generate a trans-membrane gradient, maintain cation homeostasis in cardiomyocytes and participate in regulating contractile force development. Na+-K+ ATPase serves as a receptor for both exogenous and endogenous cardiotonic glycosides and steroids, and a signal transducer for modifying myocardial metabolism as well as cellular survival and death. In addition, Na+-K+ ATPase is regulated by different hormones through the phosphorylation/dephosphorylation of phospholemman, which is tightly bound to this enzyme. The activity of Na+-K+ ATPase has been reported to be increased, unaltered and depressed in failing hearts depending upon the type and stage of heart failure as well as the association/disassociation of phospholemman and binding with endogenous cardiotonic steroids, namely endogenous ouabain and marinobufagenin. Increased Na+-K+ ATPase activity in association with a depressed level of intracellular Na+ in failing hearts is considered to decrease intracellular Ca2+ and serve as an adaptive mechanism for maintaining cardiac function. The slight to moderate depression of Na+-K+ ATPase by cardiac glycosides in association with an increased level of Na+ in cardiomyocytes is known to produce beneficial effects in failing hearts. On the other hand, markedly reduced Na+-K+ ATPase activity associated with an increased level of intracellular Na+ in failing hearts has been demonstrated to result in an intracellular Ca2+ overload, the occurrence of cardiac arrhythmias and depression in cardiac function during the development of heart failure. Furthermore, the status of Na+-K+ ATPase activity in heart failure is determined by changes in isoform subunits of the enzyme, the development of oxidative stress, intracellular Ca2+-overload, protease activation, the activity of inflammatory cytokines and sarcolemmal lipid composition. Evidence has been presented to show that marked alterations in myocardial cations cannot be explained exclusively on the basis of sarcolemma alterations, as other Ca2+ channels, cation transporters and exchangers may be involved in this event. A marked reduction in Na+-K+ ATPase activity due to a shift in its isoform subunits in association with intracellular Ca2+-overload, cardiac energy depletion, increased membrane permeability, Ca2+-handling abnormalities and damage to myocardial ultrastructure appear to be involved in the progression of heart failure.

Behavior of Hypertrophied Right Ventricle during the Development of Left Ventricular Failure Due to Myocardial Infarction.

In order to determine the behavior of the right ventricle, we have reviewed the existing literature in the area of cardiac remodeling, signal transduction pathways, subcellular mechanisms, ß-adrenoreceptor-adenylyl cyclase system and myocardial catecholamine content during the development of left ventricular failure due to myocardial infarction. The right ventricle exhibited adaptive cardiac hypertrophy due to increases in different signal transduction pathways involving the activation of protein kinase C, phospholipase C and protein kinase A systems by elevated levels of vasoactive hormones such as catecholamines and angiotensin II in the circulation at early and moderate stages of heart failure. An increase in the sarcoplasmic reticulum Ca2+ transport without any changes in myofibrillar Ca2+-stimulated ATPase was observed in the right ventricle at early and moderate stages of heart failure. On the other hand, the right ventricle showed maladaptive cardiac hypertrophy at the severe stages of heart failure due to myocardial infarction. The upregulation and downregulation of ß-adrenoreceptor-mediated signal transduction pathways were observed in the right ventricle at moderate and late stages of heart failure, respectively. The catalytic activity of adenylate cyclase, as well as the regulation of this enzyme by Gs proteins, were seen to be augmented in the hypertrophied right ventricle at early, moderate and severe stages of heart failure. Furthermore, catecholamine stores and catecholamine uptake in the right ventricle were also affected as a consequence of changes in the sympathetic nervous system at different stages of heart failure. It is suggested that the hypertrophied right ventricle may serve as a compensatory mechanism to the left ventricle during the development of early and moderate stages of heart failure.

Status of ß1-Adrenoceptor Signal Transduction System in Cardiac Hypertrophy and Heart Failure.

Although ß 1-adrenoceptor ( ß 1-AR) signal transduction, which maintains cardiac function, is downregulated in failing hearts, the mechanisms for such a defect in heart failure are not fully understood. Since cardiac hypertrophy is invariably associated with heart failure, it is possible that the loss of ß 1-AR mechanisms in failing heart occurs due to hypertrophic process. In this regard, we have reviewed the information from a rat model of adaptive cardiac hypertrophy and maladaptive hypertrophy at 4 and 24 weeks after inducing pressure overload as well as adaptive cardiac hypertrophy and heart failure at 4 and 24 weeks after inducing volume overload, respectively. Varying degrees of alterations in ß 1-AR density as well as isoproterenol-induced increases in cardiac function, intracellular Ca 2 + -concentration in cardiomyocytes and adenylyl cyclase activity in crude membranes have been reported under these hypertrophic conditions. Adaptive hypertrophy at 4 weeks of pressure or volume overload showed unaltered or augmented increases in the activities of different components of ß 1-AR signaling. On the other hand, maladaptive hypertrophy due to pressure overload and heart failure due to volume overload at 24 weeks revealed depressions in the activities of ß 1-AR signal transduction pathway. These observations provide evidence that ß 1-AR signal system is either unaltered or upregulated in adaptive cardiac hypertrophy and downregulated in maladaptive cardiac hypertrophy or heart failure. Furthermore, the information presented in this article supports the concept that downregulation of ß 1-AR mechanisms in heart failure or maladaptive cardiac hypertrophy is not due to hypertrophic process per se. It is suggested that a complex mechanism involving the autonomic imbalance may be of a critical importance in determining differential alterations in non-failing and failing hearts.

Is Intrinsic Cardioprotection a Laboratory Phenomenon or a Clinically Relevant Tool to Salvage the Failing Heart?

Cardiovascular diseases, especially ischemic heart disease, as a leading cause of heart failure (HF) and mortality, will not reduce over the coming decades despite the progress in pharmacotherapy, interventional cardiology, and surgery. Although patients surviving acute myocardial infarction live longer, alteration of heart function will later lead to HF. Its rising incidence represents a danger, especially among the elderly, with data showing more unfavorable results among females than among males. Experiments revealed an infarct-sparing effect of ischemic "preconditioning" (IPC) as the most robust form of innate cardioprotection based on the heart's adaptation to moderate stress, increasing its resistance to severe insults. However, translation to clinical practice is limited by technical requirements and limited time. Novel forms of adaptive interventions, such as "remote" IPC, have already been applied in patients, albeit with different effectiveness. Cardiac ischemic tolerance can also be increased by other noninvasive approaches, such as adaptation to hypoxia- or exercise-induced preconditioning. Although their molecular mechanisms are not yet fully understood, some noninvasive modalities appear to be promising novel strategies for fighting HF through targeting its numerous mechanisms. In this review, we will discuss the molecular mechanisms of heart injury and repair, as well as interventions that have potential to be used in the treatment of patients.

Role of phospholipase C in catecholamine-induced increase in myocardial protein synthesis.

The activation of the α1-adrenoceptor-(α1-AR) by norepinephrine results in the G-protein (Gqα) mediated increase in the phosphoinositide-specific phospholipase C (PLC) activity. The byproducts of PLC hydrolytic activity, namely, 1,2-diacylglycerol and inositol-1,4,5-trisphosphate, are important downstream signal transducers for increased protein synthesis in the cardiomyocyte and the subsequent hypertrophic response. In this article, evidence was outlined to demonstrate the role of cardiomyocyte PLC isozymes in the catecholamine-induced increase in protein synthesis by using a blocker of α1-AR and an inhibitor of PLC. The discussion was focused on the α1-AR-Gqα-PLC-mediated hypertrophic signalling pathway from the viewpoint that it may compliment the other ß1-AR-Gs protein-adenylyl cyclase signal transduction mechanisms in the early stages of cardiac hypertrophy development, but may become more relevant at the late stage of cardiac hypertrophy. From the information provided here, it is suggested that some specific PLC isozymes may potentially serve as important targets for the attenuation of cardiac hypertrophy in the vulnerable patient population at-risk for heart failure.

Future scope and challenges for congestive heart failure: moving toward development of pharmacotherapy.

Heart failure is invariably associated with cardiac hypertrophy and impaired cardiac performance. Although several drugs have been developed to delay the progression of heart failure, none of the existing interventions have shown beneficial effects in reducing morbidity and mortality. To determine specific targets for future drug development, we have discussed different mechanisms involving both cardiomyocytes and nonmyocyte extracellular matrix (ECM)) alterations for the transition of cardiac hypertrophy to heart failure as well as for the progression of heart failure. We have emphasized the role of oxidative stress, inflammatory cytokines, metabolic alterations, and Ca2+-handling defects in adverse cardiac remodeling and heart dysfunction in hypertrophied myocardium. Alterations in the regulatory process due to several protein kinases, as well as the participation of mitochondrial Ca2+ overload, activation of proteases and phospholipases, and changes in gene expression for subcellular remodeling have also been described for the occurrence of cardiac dysfunction. Association of cardiac arrhythmia with heart failure has been explained as a consequence of catecholamine oxidation products. Since these multifactorial defects in ECM and cardiomyocytes are evident in the failing heart, it is a challenge for experimental cardiologists to develop appropriate combination drug therapy for improving cardiac function in heart failure.

Modification of Ischemia/Reperfusion-Induced Alterations in Subcellular Organelles by Ischemic Preconditioning.

It is now well established that ischemia/reperfusion (I/R) injury is associated with the compromised recovery of cardiac contractile function. Such an adverse effect of I/R injury in the heart is attributed to the development of oxidative stress and intracellular Ca2+-overload, which are known to induce remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils. However, repeated episodes of brief periods of ischemia followed by reperfusion or ischemic preconditioning (IP) have been shown to improve cardiac function and exert cardioprotective actions against the adverse effects of prolonged I/R injury. This protective action of IP in attenuating myocardial damage and subcellular remodeling is likely to be due to marked reductions in the occurrence of oxidative stress and intracellular Ca2+-overload in cardiomyocytes. In addition, the beneficial actions of IP have been attributed to the depression of proteolytic activities and inflammatory levels of cytokines as well as the activation of the nuclear factor erythroid factor 2-mediated signal transduction pathway. Accordingly, this review is intended to describe some of the changes in subcellular organelles, which are induced in cardiomyocytes by I/R for the occurrence of oxidative stress and intracellular Ca2+-overload and highlight some of the mechanisms for explaining the cardioprotective effects of IP.

Modification of ischemia/reperfusion induced infarct size by ischemic preconditioning in hypertrophied hearts.

This study examined the effects of ischemic preconditioning (IP) on the ischemia/reperfusion (I/R) induced injury in normal and hypertrophied hearts. Cardiac hypertrophy in rabbits was induced by L-thyroxine (0.5 mg/kg/day for 16 days). Hearts with or without IP (3 cycles of 5 min ischemia and 10 min reperfusion) were subjected to I/R (60 min ischemia followed by 60 min reperfusion). IP reduced the I/R-induced infarct size from 68% to 24% and 57% to 33% in the normal and hypertrophied hearts, respectively. Leakage of creatine phosphokinase in the perfusate from the hypertrophied hearts due to I/R was markedly less than that form the normal hearts; IP prevented these changes. Although IP augmented the increase in phosphorylated p38-mitogen-activated protein kinase (p38-MAPK) content due to I/R, this effect was less in the hypertrophied than in the normal heart. These results suggest that reduced cardioprotection by IP of the I/R-induced injury in hypertrophied hearts may be due to reduced activation of p38-MAPK in comparison with normal hearts.

Temperature-dependent effects on CO2 water bath therapy induced changes in blood flow and vascularity in hind limb ischemia.

To test if magnitudes of the beneficial actions of CO2 water bath therapy on blood flow and vascular density are dependent upon temperature, ischemia in the hind limb of rats was induced by occluding the left femoral artery for 2 weeks and the animals were exposed to water bath therapy with or without CO2 at 34 or 41 °C for 4 weeks (20 min treatment each day for 5 days/week). CO2 water bath therapy at 34 °C increased peak, minimal, and mean blood flow by 190%-600% in the ischemic limb. On the other hand, CO2 water bath treatment at 41 °C increased these parameters of blood flow by 37%, 55%, and 41%, respectively, in the ischemic limb. The small blood vessel count, an index of vascular density, in the ischemic limb was increased by CO2 water bath therapy at 34 and 41 °C by 32% and 122%, respectively. No changes in the ischemic animals by CO2 water bath therapy at 34 or 41 °C were observed in the heart rate, R-R interval, and plasma lipid or glucose levels. These data indicate that the beneficial effect of CO2 water bath therapy at 34 °C on blood flow in the ischemic muscle is greater whereas that on vascular density is smaller than changes in these parameters at 41 °C.

Mechanisms for the transition from physiological to pathological cardiac hypertrophy.

The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes ventricular wall stress for the heart undergoing a greater than normal workload. At initial stages, cardiac hypertrophy is associated with normal or enhanced cardiac function and is considered to be adaptive or physiological; however, at later stages, if the stimulus is not removed, it is associated with contractile dysfunction and is termed as pathological cardiac hypertrophy. It is during physiological cardiac hypertrophy where the function of subcellular organelles, including the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils, may be upregulated, while pathological cardiac hypertrophy is associated with downregulation of these subcellular activities. The transition of physiological cardiac hypertrophy to pathological cardiac hypertrophy may be due to the reduction in blood supply to hypertrophied myocardium as a consequence of reduced capillary density. Oxidative stress, inflammatory processes, Ca2+-handling abnormalities, and apoptosis in cardiomyocytes are suggested to play a critical role in the depression of contractile function during the development of pathological hypertrophy.

Role of lysophosphatidic acid in vascular smooth muscle cell proliferation.

Lysophosphatidic acid (LPA) is an important lipid molecule for signal transduction in cell proliferation. Although the effects of LPA on vascular smooth muscle (VSM) cell growth have been reported previously, the underlying mechanisms of its action are not fully understood. The present study was undertaken to investigate the effects of some inhibitors of different protein kinases and other molecular targets on LPA-induced DNA synthesis as well as gene expression in the aortic VSM cells. The DNA synthesis was studied by the [3H]thymidine incorporation method and the gene expression was investigated by the real-time PCR technique. It was observed that the LPA-induced DNA synthesis was attenuated by inhibitors of protein kinase C (PKC) (staurosporine, calphostin C, and bisindolylmaleimide), phosphoinositide 3-kinase (PI3K) (wortmannin and LY294002), and ribosomal p70S6 kinase (p70S6K) (rapamycin). The inhibitors of guanine protein coupled receptors (GPCR) (pertussis toxin), phospholipase C (PLC) (U73122 and D609), and sodium-hydrogen exchanger (NHE) (amiloride and dimethyl amiloride) were also shown to depress the LPA-induced DNA synthesis. Furthermore, gene expressions for PLC ß1 isoform, PKC δ and ε isoforms, casein kinase II ß isoform, and endothelin-1A receptors were elevated by LPA. These results suggest that the LPA-induced proliferation of VSM cells is mediated through the activation of GPCR and multiple protein kinases as well as gene expressions of some of their specific isoforms.

Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy.

Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+ and impaired sensitivity of myofibrils to Ca2+. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin-angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy.

Role of Oxidative Stress in the Genesis of Ventricular Arrhythmias.

Ventricular arrhythmias, mainly lethal arrhythmias, such as ventricular tachycardia and fibrillation, may lead to sudden cardiac death. These are triggered as a result of cardiac injury due to chronic ischemia, acute myocardial infarction and various stressful conditions associated with increased levels of circulating catecholamines and angiotensin II. Several mechanisms have been proposed to underlie electrical instability of the heart promoting ventricular arrhythmias; however, oxidative stress which adversely affects ion homeostasis due to changes in the ion channel structure and function, seems to play a critical role in eliciting different types of ventricular arrhythmias. Prevention or mitigation of the severity of ventricular arrhythmias due to antioxidants has been indicated as the fundamental contribution in the field of preventive cardiology; however, novel interventions have to be developed for greater effectiveness and specificity in attenuating the adverse effects of oxidative stress. In this review, we have attempted to discuss proarrhythmic effects of oxidative stress differing in time and concentration dependence and highlight a molecular and cellular concept how it alters cardiac cell automaticity and conduction velocity sensitizing the probability of ventricular arrhythmias with resultant sudden cardiac death due to ischemic heart disease and other stressful situations. It is concluded that pharmacological approaches targeting multiple mechanisms besides oxidative stress might be more effective in the treatment of ventricular arrhythmias than current antiarrhythmic therapy.

Emerging role of non-coding RNAs and extracellular vesicles in cardioprotection by remote ischemic conditioning of the heart.

Remote ischemic conditioning of the heart (including pre-, per-, and post-conditioning) is a phenomenon where short episodes of non-lethal ischemia in the distant vessels within the heart or distant organs from the heart protects the myocardium against sustained ischemia/reperfusion injury. Several pathways have been proposed to be involved in the mechanisms of Remote ischemic conditioning. While triggers of Remote ischemic conditioning act in preconditioned areas, its mediators transduce protective signals via humoral or neuronal pathways to the heart. Remote ischemic conditioning is mediated via receptor and nonreceptor signaling through secondary mediators, which transfer the signal within the cardiomyocyte and activate cardioprotective pathways that lead to higher resistance of the heart to ischemia/reperfusion. Apparently, identification of endogenous signal molecules involved in the mechanisms of Remote ischemic conditioning have therapeutic implications in the management of patients suffering from myocardial ischemia through the development of diverse beneficial effects. Recently, different non-coding RNAs such as microRNAs or long non-coding RNAs have been identified as emerging factors that trigger protective mechanisms in the heart. These non-coding RNAs are transferred to the heart via extracellular vesicles that exert remote cardioprotection. This review is intended to summarize the existing knowledge about the potential role of extracellular vesicles as humoral transmitters of Remote ischemic conditioning and emphasize the involvement of non-coding RNAs in the mechanism of cardioprotection by Remote ischemic conditioning.

Store-operated calcium channels: Potential target for the therapy of hypertension.

Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca²âº channels to Ca²âº influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca²âº channel inhibitors and Ca²âº antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca²âº channel - the voltage independent store-operated Ca²âº channel - has been implicated in the regulation and fine tuning of Ca²âº entry in both cardiac and smooth muscle cells. Store-operated Ca²âº channels are activated by the depletion of Ca²âº stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca²âº, thereby facilitating agonist-induced Ca²âº influx. Store-operated Ca²âº entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca²âº entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of store-operated Ca²âº channels acting at the level of both STIM and Orai channels have been shown to depress Ca²âº influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca²âº channels that act in vascular smooth muscles for the improved treatment of hypertension.

Modification of gene expression in rat cardiomyocytes by linoleic and docosahexaenoic acids 1.

Regulation of cardiac fatty acid metabolism is central to the development of cardiac hypertrophy and heart failure. We investigated the effects of select fatty acids on the expression of genes involved in immediate early as well as inflammatory and hypertrophic responses in adult rat cardiomyocytes. Cardiac remodeling begins with upregulation of immediate early genes for c-fos and c-jun, followed by upregulation of inflammatory genes for nuclear factor kappa B (NF-κB) and nuclear factor of activated T-cells (NFAT). At later stages, genes involved in hypertrophic responses, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are upregulated. Adult rat cardiomyocytes were treated with palmitic acid, a saturated fatty acid; oleic acid, a monounsaturated fatty acid; linoleic acid, a polyunsaturated fatty acid belonging to the n-6 class; and docosahexaenoic acid, a polyunsaturated fatty acid belonging to the n-3 class. Linoleic acid produced a greater increase in the mRNA expression of c-fos, c-jun, NF-κB, NFAT3, ANP, and BNP relative to palmitic acid and oleic acid. In contrast, docosahexaenoic acid caused a decrease in the expression of genes involved in cardiac hypertrophy. Our findings suggest that linoleic acid may be a potent inducer of genes involved in cardiac hypertrophy, whereas docosahexaenoic acid may be protective against the cardiomyocyte hypertrophic response.

ß-1 adrenoceptors and AT1 receptors may not be involved in catecholamine-induced lethal arrhythmias 1.

An excessive amount of catecholamines produce arrhythmias, but the exact mechanisms of this action are not fully understood. For this purpose, Sprague-Dawley rats were treated with or without atenolol, a ß1-adrenoceptor blocker (20 mg/kg per day), for 15 days followed by injections of epinephrine for cumulative doses of 4 to 128 µg/kg. Another group of animals were pretreated with losartan, an angiotensin receptor (AT1) blocker (20 mg/kg per day), for comparison. Control animals received saline. Varying degrees of ventricular arrhythmias were seen upon increasing the dose of epinephrine, but the incidence and duration of the rhythm abnormalities as well as the number of episodes and severity of arrhythmias were not affected by treating the animals with atenolol or losartan. The levels of both epinephrine and norepinephrine were increased in the atenolol-treated rats but were unchanged in the losartan-treated animals after the last injection of epinephrine; the severity of arrhythmias did not correlate with the circulating catecholamine levels. These results indicate that both ß1-adrenoceptors and AT1 receptors may not be involved in the pathogenesis of catecholamine-induced arrhythmias and support the view that other mechanisms, such as the oxidation products of catecholamines, may play a crucial role in the occurrence of lethal arrhythmias.