Lipoxin A improves cardiac remodeling and function in diabetes-associated cardiac dysfunction.

Background: Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A (LXA), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought.

IL-4 and IL-13 induce equivalent expression of traditional M2 markers and modulation of reactive oxygen species in human macrophages.

In cardiovascular disease, pathological and protective roles are reported for the Th2 cytokines IL-4 and IL-13, respectively. We hypothesised that differential effects on macrophage function are responsible. Type I and II receptor subunit (IL-2Rγ, IL-4Rα and IL-13Rα1) and M2 marker (MRC-1, CCL18, CCL22) expression was assessed via RT-qPCR in IL-4- and IL-13-treated human primary macrophages.

Long-term dietary nitrate supplementation slows the progression of established atherosclerosis in ApoE mice fed a high fat diet.

Background And Aims: Atherosclerosis is associated with a reduction in the bioavailability and/or bioactivity of endogenous nitric oxide (NO). Dietary nitrate has been proposed as an alternate source when endogenous NO production is reduced. Our previous study demonstrated a protective effect of dietary nitrate on the development of atherosclerosis in the apoE mouse model.

The single-chain relaxin mimetic, B7-33, maintains the cardioprotective effects of relaxin and more rapidly reduces left ventricular fibrosis compared to perindopril in an experimental model of cardiomyopathy.

The hormone, relaxin (RLX), exerts various organ-protective effects independently of etiology. However, its complex two-chain and three disulphide bonded structure is a limitation to its preparation and affordability. Hence, a single chain-derivative of RLX, B7-33, was developed and shown to retain the anti-fibrotic effects of RLX in vitro and in vivo.

A high-sucrose diet exacerbates the left ventricular phenotype in a high fat-fed streptozotocin rat model of diabetic cardiomyopathy.

Left ventricular (LV) dysfunction is an early, clinically detectable sign of cardiomyopathy in type 2 diabetes mellitus (T2DM) that precedes the development of symptomatic heart failure. Preclinical models of diabetic cardiomyopathy are essential to develop therapies that may prevent or delay the progression of heart failure. This study examined the molecular, structural, and functional cardiac phenotype of two rat models of T2DM induced by a high-fat diet (HFD) with a moderate- or high-sucrose content (containing 88.

Post-stroke administration of H2 relaxin reduces functional deficits, neuronal apoptosis and immune cell infiltration into the mouse brain.

Brain inflammation and apoptosis contribute to neuronal damage and loss following ischaemic stroke, leading to cognitive and functional disability. It is well-documented that the human gene-2 (H2)-relaxin hormone exhibits pleiotropic properties via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), including anti-inflammatory and anti-apoptotic effects, thus making it a potential therapeutic for stroke. Hence, the current study investigated whether post-stroke H2-relaxin administration could improve functional and histological outcomes.

Cardioprotective actions of nitroxyl donor Angeli's salt are preserved in the diabetic heart and vasculature in the face of nitric oxide resistance.

Background And Purpose: The risk of fatal cardiovascular events is increased in patients with type 2 diabetes mellitus (T2DM). A major contributor to poor prognosis is impaired nitric oxide (NO•) signalling at the level of tissue responsiveness, termed NO• resistance. This study aimed to determine if T2DM promotes NO• resistance in the heart and vasculature and whether tissue responsiveness to nitroxyl (HNO) is affected.

Vasoprotective Actions of Nitroxyl (HNO): A Story of Sibling Rivalry.

Nitroxyl (HNO), the 1 electron-reduced and protonated form of nitric oxide (NO•), has emerged as a nitrogen oxide with a suite of vasoprotective properties and therapeutic advantages over its redox sibling. Although HNO has garnered much attention due to its cardioprotective actions in heart failure, its ability to modulate vascular function, without the limitations of tolerance development and NO• resistance, is desirable in the treatment of vascular disease. HNO serves as a potent vasodilator and antiaggregatory agent and has an ability to limit vascular inflammation and reactive oxygen species generation.

Defining and unpacking the core concepts of pharmacology education.

Pharmacology education currently lacks a research-based consensus on which core concepts all graduates should know and understand, as well as a valid and reliable means to assess core conceptual learning. The Core Concepts in Pharmacology Expert Group (CC-PEG) from Australia and New Zealand recently identified a set of core concepts of pharmacology education as a first step toward developing a concept inventory-a valid and reliable tool to assess learner attainment of concepts. In the current study, CC-PEG used established methodologies to define each concept and then unpack its key components.

Innovative Anti-Inflammatory and Pro-resolving Strategies for Pulmonary Hypertension: High Blood Pressure Research Council of Australia Award 2019.

Pulmonary hypertension is a rare, ostensibly incurable, and etiologically diverse disease with an unacceptably high 5-year mortality rate (≈50%), worse than many cancers. Irrespective of pathogenic origin, dysregulated immune processes underlie pulmonary hypertension pathobiology, particularly pertaining to pulmonary vascular remodeling. As such, a variety of proinflammatory pathways have been mooted as novel therapeutic targets.

IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in Mice.

IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18−/− mice by uninephrectomy, deoxycorticosterone acetate (2.

Identifying the core concepts of pharmacology education.

Pharmacology education currently lacks an agreed knowledge curriculum. Evidence from physics and biology education indicates that core concepts are useful and effective structures around which such a curriculum can be designed to facilitate student learning. Building on previous work, we developed a novel, criterion-based method to identify the core concepts of pharmacology education.

Animal models of pulmonary hypertension: Getting to the heart of the problem.

Despite recent therapeutic advances, pulmonary hypertension (PH) remains a fatal disease due to the development of right ventricular (RV) failure. At present, no treatments targeted at the right ventricle are available, and RV function is not widely considered in the preclinical assessment of new therapeutics. Several small animal models are used in the study of PH, including the classic models of exposure to either hypoxia or monocrotaline, newer combinational and genetic models, and pulmonary artery banding, a surgical model of pure RV pressure overload.

Diabetes Attenuates the Contribution of Endogenous Nitric Oxide but Not Nitroxyl to Endothelium Dependent Relaxation of Rat Carotid Arteries.

Endothelial dysfunction is a major risk factor for several of the vascular complications of diabetes, including ischemic stroke. Nitroxyl (HNO), the one electron reduced and protonated form of nitric oxide (NO•), is resistant to scavenging by superoxide, but the role of HNO in diabetes mellitus associated endothelial dysfunction in the carotid artery remains unknown. To assess how diabetes affects the role of endogenous NO• and HNO in endothelium-dependent relaxation in rat isolated carotid arteries.

Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy-induced ventricular remodelling and dysfunction.

Background And Purpose: Oxidative stress and fibrosis are hallmarks of cardiomyopathy-induced heart failure yet are not effectively targeted by current frontline therapies. Here, the therapeutic effects of the anti-oxidant, N-acetylcysteine (NAC), were compared and combined with an acute heart failure drug with established anti-fibrotic effects, serelaxin (RLX), in a murine model of cardiomyopathy.

Experimental Approach: Adult male 129sv mice were subjected to repeated isoprenaline (25 mg·kg )-induced cardiac injury for five consecutive days and then left to undergo fibrotic healing until Day 14.

Cardiovascular Therapeutic Potential of the Redox Siblings, Nitric Oxide (NO•) and Nitroxyl (HNO), in the Setting of Reactive Oxygen Species Dysregulation.

Reactive oxygen species (ROS) dysregulation is a hallmark of cardiovascular disease, characterised by an imbalance in the synthesis and removal of ROS. ROS such as superoxide (•O), hydrogen peroxide (HO), hydroxyl (OH•) and peroxynitrite (ONOO) have a marked impact on cardiovascular function, contributing to the vascular impairment and cardiac dysfunction associated with diseases such as angina, hypertension, diabetes and heart failure. Central to the vascular dysfunction is a reduction in bioavailability and/or physiological effects of vasoprotective nitric oxide (NO•), leading to vasoconstriction, inflammation and vascular remodelling.

Nitroxyl: A Novel Strategy to Circumvent Diabetes Associated Impairments in Nitric Oxide Signaling.

Diabetes is associated with an increased mortality risk due to cardiovascular complications. Hyperglycemia-induced oxidative stress underlies these complications, leading to an impairment in endogenous nitric oxide (NO•) generation, together with reductions in NO• bioavailability and NO• responsiveness in the vasculature, platelets and myocardium. The latter impairment of responsiveness to NO•, termed NO• resistance, compromises the ability of traditional NO•-based therapeutics to improve hemodynamic status during diabetes-associated cardiovascular emergencies, such as acute myocardial infarction.

The anti-fibrotic actions of relaxin are mediated through AT R-associated protein phosphatases via RXFP1-AT R functional crosstalk in human cardiac myofibroblasts.

Fibrosis is a hallmark of several cardiovascular diseases. The relaxin family peptide receptor 1 (RXFP1) agonist, relaxin, has rapidly occurring anti-fibrotic actions which are mediated through RXFP1 and angiotensin II receptor crosstalk on renal and cardiac myofibroblasts. Here, we investigated whether this would allow relaxin to indirectly activate angiotensin II type 2 receptor (AT R)-specific signal transduction in primary human cardiac myofibroblasts (HCMFs).

Targeting the NLRP3 inflammasome to treat cardiovascular fibrosis.

Cardiovascular fibrosis refers to the scar tissue that develops in the injured heart and blood vessels from an aberrant wound healing response to organ injury or insult. Established fibrosis becomes a hallmark of chronic disease progression and a key contributor to tissue stiffness and dysfunction, which ultimately leads to heart failure. As wound healing and fibrotic responses to myocardial injury are multifactorial processes, current therapies that only target specific contributing factors to disease pathogenesis offer limited overall anti-fibrotic efficacy.

An in vivo examination of the differences between rapid cardiovascular collapse and prolonged hypotension induced by snake venom.

We investigated the cardiovascular effects of venoms from seven medically important species of snakes: Australian Eastern Brown snake (Pseudonaja textilis), Sri Lankan Russell's viper (Daboia russelii), Javanese Russell's viper (D. siamensis), Gaboon viper (Bitis gabonica), Uracoan rattlesnake (Crotalus vegrandis), Carpet viper (Echis ocellatus) and Puff adder (Bitis arietans), and identified two distinct patterns of effects: i.e.

Distinct Redox Signalling following Macrophage Activation Influences Profibrotic Activity.

Aims: To date, the ROS-generating capacities of macrophages in different activation states have not been thoroughly compared. This study is aimed at determining the nature and levels of ROS generated following stimulation with common activators of M1 and M2 macrophages and investigating the potential for this to impact fibrosis.

Results: Human primary and THP-1 macrophages were treated with IFN-+LPS or IL-4-activating stimuli, and mRNA expression of established M1 (CXCL11, CCR7, IL-1) and M2 (MRC-1, CCL18, CCL22) markers was used to confirm activation.

Nitric Oxide Resistance, Induced in the Myocardium by Diabetes, Is Circumvented by the Nitric Oxide Redox Sibling, Nitroxyl.

Impairment of tissue responsiveness to exogenous and endogenous nitric oxide (NO), known as NO resistance, occurs in many cardiovascular disease states, prominently in diabetes and especially in the presence of marked hyperglycemia. In this study, we sought to determine in moderate and severe diabetes (i) whether NO resistance also occurs in the myocardium, and (ii) whether the NO redox sibling nitroxyl (HNO) circumvents this. The spectrum of acute NO effects (induced by diethylamine-NONOate), including vasodilation, and enhanced myocardial contraction and relaxation were impaired by moderately diabetic rats ([blood glucose] ∼20 m).

Venom Mediates Vasodilatation of Resistance Like Arteries via Activation of K and K Channels.

Russell's viper () venom causes a range of clinical effects in humans. Hypotension is an uncommon but severe complication of Russell's viper envenoming. The mechanism(s) responsible for this effect are unclear.