Current Pharmaceutical Design - Volume 20, Issue 9, 2014

The key oxygen sensing molecules, Prolyl-hydroxylase domain 1-3 enzymes (PHD1-3), regulate hypoxia-inducible factor (HIF) under hypoxia. In the settings of cardiomyopathy and ischemia-reperfusion injury, PHD3 expression is elevated, resulting in decreased HIF activation. The role of PHD3 in myocardial injury is poorly understood. Hence, we aimed to determine the effects of PHD3 deletion in mice on HIF-1α and other related pathways following myocardial infarction (MI). Left coronary artery (LAD) in both wild type and prolyl hydroxylase 3 knock out (PHD3-/-) mice was ligated to induce myocardial infarction. Electrophoretic mobility shift analysis showed significant increase in DNA-binding activity of HIF-1α in PHD3-/- mice as compared to wild type (WT) mice post MI. The PHD3-/-MI group also showed decreased fibrosis. Seven days after MI, enhanced capillary / arteriolar density was observed compared to WTMI group. PHD3-/- mice subjected to MI also showed improved cardiac functions (Ejection fraction and Fractional shortening), as assessed by echocardiogram, compared to WT. Western blot analysis showed increased VEGF, Ang-1 & Bcl-2 expression in PHD3-/-MI group. In conclusion, ablation of the PHD3 gene resulted in increased angiogenesis and cardiac function after infarction thereby offering a potential target for pharmacological management of ischemic myocardial disease.

Inflammation reduces pharmacological response to β1-blockers by down-regulating the target receptor protein. This may contribute to the sub-optimal response to pharmacotherapy with β-blockers. Nebivolol is a third generation β-adrenoceptor (AR) blocker with high selectivity for blocking β1 and β3-agonistitic properties. We studied whether response to nebivolol is also reduced by inflammation. Male Sprague-Dawley rats (Inflamed; Mycobacterium butyricum induced) and Control (healthy) were orally administered single doses of 2 mg/kg nebivolol (n=5) or 25 mg/kg propranolol (positive control, n=7-8); ECG recorded for PR and RR interval measurements; serial blood samples were collected for pharmacokinetic assessment. Subsequently, the myocardial β1, β2 and β3-AR levels were measured in homogenized hearts. For propranolol, inflammation resulted in increased concentration but reduced response and down-regulation of β1- AR. The action and disposition of nebivolol were, however, unaffected by inflammation despite the reduced β1-AR levels. The levels of β2 and β3-AR were unaffected by inflammation. The consistency of response to nebivolol despite inflammation may be due to the predominance of contribution of β2 and β3-AR. The lack of an inhibitory effect of inflammation on the clearance of nebivolol is suggestive of mechanisms other than an efficient hepatic metabolism for its low bioavailability. If extrapolated to human, nebivolol may be a more effective cardiovascular drug when inflammatory conditions are present.

Although recent studies have underscored the role of the heme-oxygenase (HO) inducer hemin, on insulin-signaling and glucose metabolism, the underlying mechanisms are not completely understood. In this study, two-dimensional-gel electrophoresis, massspectrometry and MSACOT-analyses were used to identify and characterize novel proteins modulated by hemin in spontaneoushypertensive rat (SHR), a model of essential hypertension with insulin resistance/impaired glucose metabolism. In addition, the effects of hemin on endothelin-1 (ET-1), protein-tyrosine-phosphatase-1B (PTP-1B), atrial-natriuretic-peptide (ANP) and its surrogate-marker urinary cGMP, and inflammatory cytokines including TNF-α, IL-6 and IL-1β were investigated. In hemin-treated SHR, several proteins related to oxidative-stress and metabolism were modulated. Particularly, hemin enhanced aldolase- B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase and carbonic anhydrase-3 all of which are enzymes involved in glucose/energy metabolism and pH homeostasis. Similarly, hemin potentiated antioxidant pathways including, NADP(+)-dependant isocitrate-dehydrogenase, catalase, glutathione-S-transferase-Yb1 and hsp70, a pleiotropic agent that regulates protein-folding, oxidative/pro-inflammatory events. Hemin also increased enzymes implicated in cell-growth such as the nitrilase-protein-family, but reduced betaine-homocysteine methyltransferase, an enzyme associated with insulin resistance and dysfunctional glucose metabolism. Furthermore, hemin increased ANP and its surrogate marker, urinary cGMP, but reduced ET-1, PTP-1B, TNF-α, IL-6, IL-1β, whereas the HO-inhibitor, chromium-mesoporphyrin abolished the effects. The potentiation of ANP, urinary-cGMP, aldolade-B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase, carbonic anhydrase-3, hsp70 and the corresponding reduction of betaine-homocysteine methyltransferase, PTP-1B, TNF-α, IL-6, IL-1β, and ET-1 may be responsible for the improved glucose metabolism in hemin-treated animals. Collectively, these findings underscore the pleiotropic effects of the HO-system in cellular homeostasis with important roles in metabolism and defence.

Diabetes is a complex endocrine/metabolic disease with many related complications including micro-vascular and macrovascular problems such as cardiomyopathy, nephropathy, neuropathy and retinopathy. Generally, type-1 diabetes is caused by autoimmune- mediated destruction of pancreatic beta cells leading to insulin deficiency. This is usually accompanied by dyslipidemia, enhanced hyperglycemia-mediated oxidative stress, endothelial-cell dysfunction and apoptosis. For decades, type-1 diabetes has been traditionally known as insulin-dependent, while type-2 as non-insulin dependent diabetes. However, it is becoming increasingly clear that insulin deficiency and insulin resistance are manifested in both forms of diabetes at different stages. Thus, it may be time revisit the nomenclature and adjust it to reflect these observations of insulin deficiency and insulin resistance in both forms of diabetes to avoid ambiguity when discussing forms of diabetes. Emerging evidence indicates that the heme-oxygenase (HO) system and related products including carbon monoxide, ferritin and biliverdin are capable of suppressing immune/inflammatory response, and abate oxidative stress and apoptosis. More importantly, upregulating the HO-system increases pancreatic beta-cell insulin release and reduce hyperglycemia in different diabetic models. Similarly, carbon monoxide, a product of the HO-catalyzed degradation of heme also enhances insulin production and improves glucose metabolism. Since excessive immune/inflammatory responses coupled to elevated apoptosis are among the cardinal pathophysiological features of type-1 diabetes, this review highlights the role of the HO-system and related products such as carbon monoxide and bilirubin in the modulation of apoptosis and immune response, and the beneficial effects of the HO-system in the pathogenesis of type-1 diabetes and related cardiometabolic complications.

The histamine H4 receptor (H4R), recently cloned and identified, is a G-protein coupled histamine receptor family expressed in immune cells which plays an important role in inflammation. Recent data evidentiated that H4R antagonists can decrease airway inflammation and hyperreactivity in animal models of asthma. In the present study we evaluated the effect of the selective H4R antagonist JNJ7777120 (JNJ) in carrageenan-induced pleurisy, an in vivo model of inflammation, well characterized for cellular and molecular mechanisms. Intra-pleural administration of λ-carrageenan (1% w/v in 0.2 ml sterile saline) determined an intense recruitment of leucocytes in pleural exudates and in lung tissues, activated inducible nitric oxide (NO) synthase and cyclooxygenase-2, thus increasing the generation of harmful autacoids such as NO and pro-inflammatory prostaglandins, PgE2 and 6-ketoPgF1α, increased cellular and DNA oxidative stress, measured as malondialdehyde and 8-OH-deoxyguanosine and the local generation of IL-1β and TNF-α. Moreover, the activity of caspase-3, an early marker of apoptosis was also activated by λ-carrageenan injection. The pre-treatment with JNJ (5-10 mg Kg-1 b.wt., given intrapleurally), 60 min before carrageenan markedly reduced all the studied parameters. This study clearly demonstrated that histamine H4R antagonists have anti-inflammatory effects and could have potential therapeutic application for the treatment of inflammatory diseases.

Cardiac ischemia, followed by reperfusion, often results in the development of cardiac contractile dysfunction that limits the recovery prognosis of patients. The current goal of pharmacological therapy in the course of ischemic heart disease is to improve the oxygen supply/demand ratio for the heart. Cardiac contractile proteins such as myosin light chain 1 and 2 (MLC1 and MLC2) and troponin I, play a significant role in the regulation of force development. It has been shown that MLC1 can be nitrated, S-nitrosylated, as well as phosphorylated. These posttranslational modifications (PTMs) of MLC1 are associated with an increase in the affinity for the proteolytic enzyme matrix metalloproteinase-2 (MMP-2) resulting in an increased degradation of MLC1 that corresponds with the development of cardiac contractile dysfunction. The degree of MLC1 degradation is associated with the degree of mechanical dysfunction in the ischemic heart. Pharmacological regulation of the PTM status of cardiac contractile proteins can be achieved by inhibition of phosphorylation, nitration, or S-nitrosylation. Most pharmacological approaches for protecting the heart against ischemia/reperfusion (I/R) injury are based on the use of a single drug at full protective dose, targeting only a single molecular mechanism involved in the development of contractile dysfunction. As such, this approach often creates side effects associated with interruption of normal physiological processes. It is hypothesized that simultaneous pharmacological reduction of reactive oxygen species (ROS)-dependent PTMs of contractile proteins such as nitration/nitrosylation and/or phosphorylation, together with the pharmacological inhibition of the activity of MMPs, will protect the heart from I/R injury through synergistic or additive drug effects while also enabling lower doses to reduce interruption of normal physiological processes and limit side effects.

The pathophysiology of endotoxic shock is complex. This review emphasizes the role of reactive oxygen species (ROS) in the pathophysiology of endotoxic shock and the effectiveness of flaxseed in amelioration of the deleterious effects of endotoxic shock on the cardiovascular function and health of the tissue. Endotoxic shock is associated with reduction in the cardiac function measured by cardiac index and left ventricular work index, cardiac contractility measured by dp/dt (rate of change of left ventricular pressure development), dp/dt at CPIP/PAW, where CPIP is common peak isovolumetric pressure and PAW is pulmonary arterial wedge pressure, arterial pressure, and cellular damage measured by increased plasma creatine kinase and elavated plasma lactate. It is also accompanied by increases in the generation of ROS by polymorphonuclear leukocytes, and cardiac lipid peroxidation product malondialdehyde (MDA) (cardiac MDA) and reduction in antioxidant reserve and antioxidant enzyme activity. Dimethylthiourea an antioxidant, prevented/reduced the endotoxic shock-induced changes in the cardiac function and contractility, arterial pressure, ROS generated by polymorphonuclear leucocytes; MDA, antioxidant reserve and antioxidant enzyme activity of cardiac tissue, and cellular health. Flaxseed which has antioxidant component ameliorated the endotoxic shock-induced changes in the cardiac function and contractility, arterial pressure, oxidative stress parameters and cellular health. In conclusion, the data suggest that ROS may play a role in the pathophysiology of endotoxic shock and that flaxseed, an antioxidant may have a role in the treatment of endotoxic shock.

Hypertension is a complex interplay of interrelated etiologies, and the leading risk factor for many cardiovascular morbidity and mortality worldwide. Cardinal pathophysiological features of hypertension include enhanced vascular inflammation, vascular remodeling, vascular contractility and increased oxidative stress. In response to oxidative, inflammatory or other noxious stimuli, many physiological pathways like the heme oxygenase (HO) system are activated in an attempt to counteract tissue insults. However, the pathophysiological activation of the HO system only results to a transient increase of HO activity that fall below the necessary threshold capable of activating the downstream signaling components of the HO system like the soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) secondary messenger system. Therefore, a more robust potentiation of the HO system by pharmacological agents such as hemin, heme-arginate, cobalt protoporphyrin or through retroviral HO-1 gene delivery would be needed to surmount the threshold for cytoprotection. The HO system modulates cellular homeostasis. Importantly, the HO system plays a vital role in a wide spectrum of physiologic including the regulation of blood vessel tone. Alterations in the activity and expression of HO has been correlated to pathophysiology of hypertension and related complications such as hypertrophy, myocardial infarction and heart failure. Moreover, the cytoprotection exerted by HO is attributable to its catabolic products namely, carbon monoxide, bilirubin/biliverdin, and ferritin that are known to modulate immune, inflammatory and oxidative insults. The growing incidence of hypertension and associated cardiometabolic complications has prompted the need for the exploration of alternative therapeutic strategies like substances capable of potentiating the HO system. This review briefly, highlights the functional significance of the HO system and its downstream signaling molecules including bilirubin/biliverdin, carbon monoxide and ferritin as potential therapeutic modalities for the management of hypertension and its related co-morbid conditions.

The increased prevalence of diabetes and associated complications presents a major health risk worldwide, and requires an efficient management protocol. Type-1 and type-2 diabetes have several common pathophysiological denominators including hyperglycemia, elevated oxidative stress, increased inflammation and apoptosis. These pathological factors are implicated in the progression and worsening of the disease, and the related cardiometabolic complications associated with it. Despite the advancement in management of type-1 and type-2 diabetes, the high incidence of diabetes and related complications calls for novel therapeutic strategies. Recent findings suggest that the pharmacological modulation of the microsomal heme oxygenase (HO) system may be an important therapeutic avenue to explore. The HO system and related products such as carbon monoxide, bilirubin, biliverdin, biliverdin reductase and ferritin have been shown to abate inflammation, oxidative stress, and apoptosis and reduce hyperglycemia. In addition, the HO system also enhances insulin sensitivity and increase pancreatic beta cell insulin production in experimental models of type-1 and type-2 diabetes. This review is an effort to provide evidence of the regulatory and cytoprotective role of the HO system in type-1 and type-2 diabetes, and will highlight the multifaceted mechanisms implicated in the anti-diabetic effects of the HO system.

In order to maintain an ideal body weight, an organism must balance energy intake with energy expenditure. It is well known that metabolic signals derived in the periphery act in well-defined hypothalamic and brainstem neuronal circuits to control energy homeostasis. As such, peripheral signals that convey information regarding nutritional and metabolic status of the individual must be able to access and control these neuronal circuits in order to direct both food intake and energy expenditure. Within the hypothalamus, the arcuate nucleus of the hypothalamus has become recognized as a critical center in this integrated circuitry. Although there is considerable anatomical evidence indicating that the arcuate is protected by the blood brain barrier, neurons in this region have been repeatedly suggested to directly sense many circulating signals which do not readily diffuse across this barrier. In this review we will describe the hypothalamic circuitry involved in the regulation of energy homeostasis and will discuss data indicating that the arcuate nucleus is, in fact, protected by the blood brain barrier. We will then consider alternative mechanisms through which one specific circulating adipokine, leptin, can gain access to and influence central nervous sites involved in the regulation of energy homeostasis without the requirement for direct access from the peripheral circulation to arcuate neurons.

The Acute Respiratory Distress Syndrome (ARDS) is a highly fatal pro-inflammatory oxidative respiratory disease. Relatively recently, the modulating effects of chronic inflammatory processes on ARDS susceptibility have been recognized in a number of clinical studies. Herein, we briefly review some of the chronic conditions that have been reported to increase (cigarette smoking and alcohol abuse) or decrease (diabetes and obesity) susceptibility to ARDS. We also propose some potential pathways that may hold clues regarding the pathogenesis and/or therapy for ARDS.

The growing incidence of obesity and related complications such as cardiomyopathy and nephropathy remains a global health challenge. Many pathophysiological factors including inflammation, oxidative stress and endothelial dysfunction are implicated in obesity- induced abnormalities in the heart and kidney. Moreover, obesity and nutrient-overload are associated with the activation of different inflammatory/oxidative signaling pathways such as endoplasmic reticulum stress, nuclear factor-kappaB (NF-κB), toll-like-receptor-4 (TLR4) and the renin-angiotensin-aldosterone system (RAAS). The pathophysiological role of RAAS, TLR4 and NF-κB in perturbing physiological milieu is well acknowledged. Several pharmacological agents have been formulated to target one or more of these pathways. Although significant strides have been made in elucidating mechanisms implicated in obesity-related cardio-renal diseases, much still has to be done. The pathophysiology of cardiomyopathy and nephropathy is complex and multifaceted. Besides NF-κ B, TLR4, RAAS and inflammatory mediators such as cytokines and chemokines, a wide spectrum of different factors including, the environment, diets, lifestyles, genetics and epigenetics are also involved. With such multifactorial etiology, it remains a daunting challenge to identify the factor(s) that initiate the activation and propagation of adverse stimuli that eventually lead to cardiomyopathy and/or nephropathy in obese individuals. Similarly, the mechanisms of such activation and propagation should be clearly elucidated. Should these hurdles be overcome, there would be a greater likelihood for the development of more-effective therapeutic strategies for the prevention, treatment and management of obesity-induced cardiomyopathy and nephropathy. The present review examines the role of inflammation, oxidative stress and endothelial dysfunction in obesity-induced abnormalities in heart and kidney.