FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6.

Restenosis following endovascular intervention in lower extremity arterial disease contributes to significant morbidity and mortality. This study investigates the role of formylpeptide receptor 2 (FPR2) in neointimal hyperplasia and evaluates the therapeutic potential of the selective FPR2 agonist BMS-986235 in mitigating restenosis. FPR2 expression was significantly reduced in the popliteal and anterior tibial arteries of male amputees with restenosis compared to healthy controls.

Annexin-A1 deficiency uncovers female-specific pathways in blood pressure control and cardiovascular remodeling in mice.

Cardiovascular disease exhibits distinct sex-based differences, yet the mechanisms underlying these differences remain under-explored. The pro-resolving mediator annexin-A1 (ANXA1) is a pivotal regulator in inflammation resolution and tissue homeostasis, including within the cardiovascular system. However, the sex-specific differences in ANXA1 in blood pressure regulation have not been investigated.

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.

Biased receptor signalling and intracellular trafficking profiles of structurally distinct formylpeptide receptor 2 agonists.

Background: There is increasing interest in developing FPR2 agonists (compound 43, ACT-389949 and BMS-986235) as potential pro-resolving therapeutics, with ACT-389949 and BMS-986235 having entered phase I clinical development. FPR2 activation leads to diverse downstream outputs. ACT-389949 was observed to cause rapid tachyphylaxis, while BMS-986235 and compound 43 induced cardioprotective effects in preclinical models.

Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage.

Aims: Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.

Formyl peptide receptor 1 mitigates colon inflammation and maintains mucosal homeostasis through the inhibition of CREB-C/EBPβ-S100a8 signaling.

Excessive inflammatory responses are the main characteristic of ulcerative colitis (UC). Activation of formyl peptide receptor 1 (FPR1) has been found to promote the proliferation and migration of epithelial cells, but its role and therapeutic potential in UC remain unclear. This study observed an increased expression of FPR1 in a mouse model of colitis.

The pro-resolving mediator, annexin A1 regulates blood pressure, and age-associated changes in cardiovascular function and remodeling.

Aging is associated with chronic, low-level inflammation which may contribute to cardiovascular pathologies such as hypertension and atherosclerosis. This chronic inflammation may be opposed by endogenous mechanisms to limit inflammation, for example, by the actions of annexin A1 (ANXA1), an endogenous glucocorticoid-regulated protein that has anti-inflammatory and pro-resolving activity. We hypothesized the pro-resolving mediator ANXA1 protects against age-induced changes in blood pressure (BP), cardiovascular structure and function, and cardiac senescence.

The small-molecule formyl peptide receptor biased agonist, compound 17b, is a vasodilator and anti-inflammatory in mouse precision-cut lung slices.

Background And Purpose: Pulmonary arterial hypertension (PAH), a rare fatal disorder characterised by inflammation, vascular remodelling and vasoconstriction. Current vasodilator therapies reduce pulmonary arterial pressure but not mortality. The G-protein coupled formyl peptide receptors (FPRs) mediates vasodilatation and resolution of inflammation, actions possibly beneficial in PAH.

Endothelium-dependent relaxation is impaired in Schlager hypertensive (BPH/2J) mice by region-specific mechanisms in conductance and resistance arteries.

Aims: Endothelial dysfunction and arterial stiffness are hallmarks of hypertension, and major risk factors for cardiovascular disease. BPH/2J (Schlager) mice are a genetic model of spontaneous hypertension, but little is known about the vascular pathophysiology of these mice and the region-specific differences between vascular beds. Therefore, this study compared the vascular function and structure of large conductance (aorta and femoral) and resistance (mesenteric) arteries of BPH/2J mice with their normotensive BPN/2J counterparts.

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.

Novel strategies to promote resolution of inflammation to treat lower extremity artery disease.

Lower extremity artery disease (LEAD) is a chronic inflammatory disease that occurs when atherosclerotic plaques form in the lower extremities, which may lead to amputation if not manged properly. Given clinical standardcare (pharmacological and surgical) have limited efficacy in LEAD, developing novel strategies to manage LEAD remains an unmet clinical need. Given that active resolution of inflammation is essential to facilitate tissue healing and repair, failure to resolve inflammation may lead to chronic inflammation, dysregulated cellular homeostasis and adverse tissue remodeling.

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.

NP202 treatment improves left ventricular systolic function and attenuates pathological remodelling following chronic myocardial infarction.

Aims: Myocardial injury is a major contributor to left ventricular (LV) remodelling activating neurohormonal and inflammatory processes that create an environment of enhanced oxidative stress. This results in geometric and structural alterations leading to reduced LV systolic function. In this study we evaluated the efficacy of NP202, a synthetic flavonol, on cardiac remodelling in a chronic model of myocardial infarction (MI).

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.

Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments.

Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia.

Current state and future perspective of cardiovascular medicines derived from natural products.

The contribution of natural products (NPs) to cardiovascular medicine has been extensively documented, and many have been used for centuries. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Over the past 40 years, approximately 50% of newly developed cardiovascular drugs were based on NPs, suggesting that NPs provide essential skeletal structures for the discovery of novel medicines.

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.

Therapeutic Potential of Lipoxin A in Chronic Inflammation: Focus on Cardiometabolic Disease.

Several studies have shown that failure to resolve inflammation may contribute to the progression of many chronic inflammatory disorders. It has been suggested targeting the resolution of inflammation might be a novel therapeutic approach for chronic inflammatory diseases, including inflammatory bowel disease, diabetic complications, and cardiometabolic disease. Lipoxins [LXs] are a class of endogenously generated mediators that promote the resolution of inflammation.

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).

Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride.

Purpose: The aim of this study was to investigate the effects of the type-4 dipeptidyl peptidase (DPP-4) inhibitors linagliptin and vildagliptin as well as the sulfonylurea glimepiride on endothelium-dependent relaxation of aortae from female db/db mice with established hyperglycemia to determine whether these treatments were able to attenuate diabetes-induced endothelial dysfunction.

Materials And Methods: The mice were treated with glimepiride (2 mg/kg po per day, weeks 1-6, n=12), glimepiride plus vildagliptin (glimepiride 2 mg/kg po per day, weeks 1-6; vildagliptin 3 mg/kg po per day, weeks 4-6, n=11), glimepiride plus linagliptin (glimepiride 2 mg/kg po per day, weeks 1-6; linagliptin 3 mg/kg po per day, weeks 4-6, n=11) or linagliptin (3 mg/kg po per day, weeks 1-6, n=12). Endothelium-dependent relaxation using acetylcholine was assessed in the absence and presence of pharmacological tools (TRAM-34 1 μM; apamin 1 μM; N-nitro-L-arginine [L-NNA] 100 μM; 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one [ODQ] 10 μM) to distinguish relaxation mediated by nitric oxide (NO).

Tocomin Restores Endothelium-Dependent Relaxation in the Diabetic Rat Aorta by Increasing NO Bioavailability and Improving the Expression of eNOS.

We aimed to determine whether tocomin, an extract from palm oil that has a high tocotrienol content, was able to prevent diabetes-induced endothelial dysfunction. To induce type 1 diabetes streptozotocin (50 mg/kg) was injected into the tail vein of Wistar rats. Six weeks later the diabetic rats, and normal rats injected with citrate buffer, commenced treatment with tocomin (40 mg/kg/day sc) or its vehicle (peanut oil) for a further 4 weeks.

Shear stress sensitizes TRPV4 in endothelium-dependent vasodilatation.

The aim of this study was to better understand the role of TRPV4 in the regulation of blood vessel dilatation by blood flow and activation of GPCRs. Using pressure myography, the dilator responses to the TRPV4 agonist GSK1016790A and to acetylcholine, were examined in rat cremaster arterioles exposed to either no shear stress or to 200 μl/min flow for 6 min. In control vessels GSK1016709A caused vasodilatation (pEC 7.

Flavonols and Flavones - Protecting Against Myocardial Ischemia/Reperfusion Injury by Targeting Protein Kinases.

In acute myocardial infarction (AMI), the first line of treatment is to rapidly restore blood flow to the ischemic myocardium to limit infarct size. It is now well established that though clearly beneficial, the positive outcomes of this intervention are limited by injury in response to the reperfusion itself in addition to the prior ischemia. This process is described as reperfusion injury and is considered to contribute to the arrhythmias, microvascular dysfunction and impaired cardiac contractility that is observed even after the restoration of coronary blood flow.

Protection against reperfusion injury by 3',4'-dihydroxyflavonol in rat isolated hearts involves inhibition of phospholamban and JNK2.

Background: Flavonols, including 3',4'-dihydroxyflavonol (DiOHF), reduce myocardial ischemia and reperfusion (I/R) injury but their mechanism remains uncertain. To better understand the mechanism of the cardioprotective actions of flavonols we investigated the effect of DiOHF on cardiac function and the activation of protective and injurious signalling kinases after I/R in rat isolated hearts.

Methods: We assessed the effect of global ischemia (20min) and reperfusion (5-30min) on cardiac function and injury in rat isolated, perfused hearts in the absence or presence of DiOHF (10μM) during reperfusion.