European Journal of Pharmacology (v.763, #PA)

Preface by Niels P. Riksen; Gerard A. Rongen (1-2).

The renin–angiotensin system and its involvement in vascular disease by Bibi S. van Thiel; Ingrid van der Pluijm; Luuk te Riet; Jeroen Essers; A.H. Jan Danser (3-14).
The renin–angiotensin system (RAS) plays a critical role in the pathogenesis of many types of cardiovascular diseases including cardiomyopathy, valvular heart disease, aneurysms, stroke, coronary artery disease and vascular injury. Besides the classical regulatory effects on blood pressure and sodium homoeostasis, the RAS is involved in the regulation of contractility and remodelling of the vessel wall. Numerous studies have shown beneficial effect of inhibition of this system in the pathogenesis of cardiovascular diseases. However, dysregulation and overexpression of the RAS, through different molecular mechanisms, also induces, the initiation of vascular damage. The key effector peptide of the RAS, angiotensin II (Ang II) promotes cell proliferation, apoptosis, fibrosis, oxidative stress and inflammation, processes known to contribute to remodelling of the vasculature. In this review, we focus on the components that are under the influence of the RAS and contribute to the development and progression of vascular disease; extracellular matrix defects, atherosclerosis and ageing. Furthermore, the beneficial therapeutic effects of inhibition of the RAS on the vasculature are discussed, as well as the need for additive effects on top of RAS inhibition.
Keywords: Renin–angiotensin system; Angiotensin II; Reactive oxygen species; Vascular disease; Extracellular matrix; Atherosclerosis; Ageing; Therapeutic intervention;

Drug induced hypertension – An unappreciated cause of secondary hypertension by Alon Grossman; Franz H. Messerli; Ehud Grossman (15-22).
Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent.We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.
Keywords: Medications; Drug-induced hypertension; Blood pressure; chemicals; Tyrosine kinase inhibitors;

Baropacing as a new option for treatment of resistant hypertension by Teba Alnima; Peter W. de Leeuw; Abraham A. Kroon (23-27).
Electrical carotid baroreflex activation therapy is an emerging device-based treatment for patients with resistant hypertension. Its blood pressure lowering effect has been demonstrated in several animal and human studies, with prolonged effect over the long-term. The main mechanism of the blood pressure reduction during this therapy is by inhibition of the sympathetic outflow. Yet the question arises whether the inhibition of central sympathetic activity is sufficient to be the sole mechanism behind the sustained reduction in blood pressure. The major focus of this review is to elucidate the mechanisms of action that account for the effects of continuous carotid baroreflex activation on blood pressure in humans. Recent results of baroreflex activation therapy as a treatment for heart failure will also be discussed.
Keywords: Baroreflex activation therapy; Resistant hypertension; Carotid baroreflexes;

Obstructive sleep apnea (OSA), present in ~15% of the general population, increases the risks of stroke, heart failure, and premature death. Importantly, individuals with cardiovascular disease have a higher prevalence yet they often have few symptoms to alert clinicians to its presence. OSA with an apnea–hypopnea index (AHI) ≥15 events/hour is present in ≥30% of patients with primary hypertension and in up to 80% of those with drug resistant hypertension, suggesting that the neural, hormonal, inflammatory and vascular cascades triggered by OSA may elevate blood pressure chronically. The purpose of this review is to summarize: (1) the epidemiology of OSA and its relation to cardiovascular risk; (2) potential mechanisms by which OSA could promote conditions known to increase the risk of hypertension or contribute to its development and progression; (3) evidence for and against a pro-hypertensive effect of OSA; and, (4) the impact of treatment with continuous positive airway pressure (CPAP) on blood pressure and blood pressure-related morbidities. The prevailing view that the effect of treatment on blood pressure is modest arises from the inability of most contemporary technology to measure accurately the true impact of CPAP on OSA-entrained surges in nocturnal blood pressure. Moreover the exclusive focus on blood pressure, as if this is the principal determinant of cardiovascular event rates in this population, is naïve. The capacity to reduce cardiovascular risk by treating OSA with CPAP likely transcends a simple blood pressure effect; formal testing of this hypothesis will require adequately powered randomized clinical trials.
Keywords: Atherosclerosis; Blood pressure; Continuous positive airway pressure; Hypertension; Hypertrophy; Obstructive sleep apnea; Sleep;

PCSK9 inhibitors: Novel therapeutic agents for the treatment of hypercholesterolemia by Rutger Verbeek; Robert M. Stoekenbroek; G. Kees Hovingh (38-47).
Reducing plasma levels of low-density lipoprotein cholesterol (LDL-c) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, a substantial proportion of patients fail to achieve acceptable LDL-c levels with currently available lipid-lowering drugs. Over the last decade, inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) has emerged as a promising target to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the LDL receptor for lysosomal degradation. Inhibition of PCSK9 increases expression of the LDL receptor. This observation has led to the development of a number of approaches to directly target PCSK9. Three monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials involving various patient categories on different background lipid lowering therapies. Current evidence shows reductions in LDL cholesterol levels of up to 70%, independent of background statin therapy. The results of phase 3 trials will demonstrate the long-term efficacy and safety of PCSK9 inhibition, and will indicate whether LDL-c lowering induced by this novel approach translates into beneficial effects on CVD outcome.
Keywords: PCSK9; Proprotein Convertase Subtilisin/Kexin type 9; Alirocumab; Evolocumab; Bococizumab;

Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials.Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area (R 2=0.258, P=0.045; R 2=0.760, P<0.001), but not for HDL-C (R 2=0.030, P=0.556). In clinical trials, non-fatal myocardial infarction risk was significantly less in the treatment group with pooled odd ratios of 0.87 [0.81; 0.94] for all trials and 0.85 [0.78; 0.93] after excluding some trials due to off-target adverse events, whereas all-cause mortality was not affected (OR 1.05 [0.99–1.10]). Meta-regression analyses revealed a trend towards an association between between-group differences in absolute change from baseline in LDL-C and non-fatal myocardial infarction (P=0.066), whereas no correlation was found for HDL-C (P=0.955).We conclude that the protective role of lowering LDL-C and non-HDL-C is well-established. The contribution of raising HDL-C on inhibition of atherosclerosis and the prevention of cardiovascular disease remains undefined and may be dependent on the mode of action of HDL-C-modification. Nonetheless, treatment strategies aimed at improving HDL function and raising apolipoprotein A-I may be worth exploring.
Keywords: Cardiovascular disease; Clinical outcome; Myocardial infarction; LDL-cholesterol; Non-HDL-cholesterol; HDL-cholesterol; Atherosclerosis; Clinical trials; APOE*3Leiden.CETP mice; Mouse; Rabbit; Hamster; Niacin; Fibrates; Glitazones; PPAR agonists; CETP inhibition; SR-BI inhibitor; ABCA1 degradation inhibitors; Reconstituted HDL; Delipidated HDL; Apolipoprotein A-I Milano; Apolipoprotein A-I mimetic; Apolipoprotein A-I inducer; LCAT; HDL-C-raising pharmaceutical interventions; Preclinical studies; Systematic review; Randomised controlled trials; Meta-analysis;

New targets to treat obesity and the metabolic syndrome by Kathleen A. Martin; Mitra V. Mani; Arya Mani (64-74).
Metabolic syndrome (MetS) is a cluster ofassociated metabolic traits that collectively confer unsurpassed risk for development of cardiovascular disease (CVD) and type 2 diabetes compared to any single CVD risk factor. Truncal obesity plays an exceptionally critical role among all metabolic traits of the MetS. Consequently, the prevalence of the MetS has steadily increased with the growing epidemic of obesity. Pharmacotherapy has been available for obesity for more than one decade, but with little success in improving the metabolic profiles.The serotonergic drugs and inhibitors of pancreatic lipases were among the few drugs that were initially approved to treat obesity. At the present time, only the pancreatic lipase inhibitor orlistat is approved for long-term treatment of obesity. New classes of anti-diabetic drugs, including glucagon-like peptide 1 receptor (GLP-1R) agonists and Dipeptidyl-peptidase IV (DPP-IV) inhibitors, are currently being evaluated for their effects on obesity and metabolic traits. The genetic studies of obesity and metabolic syndrome have identified novel molecules acting on the hunger and satiety peptidergic signaling of the gut-hypothalamus axis or the melanocortin system of the brain and are promising targets for future drug development. The goal is to develop drugs that not only treat obesity, but also favorably impact its associated traits.
Keywords: Humans; Obesity; Metabolic syndrome; Diabetes; Therapeutics; Drugs; Targets;

About the gut microbiome as a pharmacological target in atherosclerosis by Julia J. Witjes; Daniel H. van Raalte; Max Nieuwdorp (75-78).
The contribution of intestinal bacterial strains (gut microbiota) in the development of cardiometabolic disease is increasingly recognized as potential diagnostic and pharmacological target. Changes in the intestinal bacterial composition and subsequent altered diversity has been associated with presence of chronic low-grade inflammation of mesenteric visceral adipose tissue, a known feature of malign obesity which can eventually lead to insulin resistance and type 2 diabetes mellitus. However, causality still needs to be proven. In this regard, both fecal transplantation studies as well as multiethnic prospective cohorts can help to identify the causally involved driving intestinal bacterial strains in human cardiometabolism. Ultimately, it is expected that novel diagnostic markers as well as therapeutics (pharmabiotics and vaccine strategies) can be developed.
Keywords: Chronic inflammation; Insulin resistance; Intestinal microbiota; Visceral adipose tissue; Trained immunity; Bacterial translocation; Probiotics; Vaccination;

Epigenetic pathways in macrophages emerge as novel targets in atherosclerosis by Annette E. Neele; Jan Van den Bossche; Marten A. Hoeksema; Menno P.J. de Winther (79-89).
Atherosclerosis is a lipid-driven chronic inflammatory disorder. Monocytes and macrophages are key immune cells in the development of disease and clinical outcome. It is becoming increasingly clear that epigenetic pathways govern many aspects of monocyte and macrophage differentiation and activation. The dynamic regulation of epigenetic patterns provides opportunities to alter disease-associated epigenetic states. Therefore, pharmaceutical companies have embraced the targeting of epigenetic processes as new approaches for interventions. Particularly histone deacetylase (Hdac) inhibitors and DNA-methyltransferase inhibitors have long received attention and several of them have been approved for clinical use in relation to hematological malignancies. The key focus is still on oncology, but Alzheimer's disease, Huntington's disease and inflammatory disorders are coming in focus as well. These developments raise opportunities for the epigenetic targeting in cardiovascular disease (CVD). In this review we discuss the epigenetic regulation of the inflammatory pathways in relation to atherosclerosis with a specific attention to monocyte- and macrophage-related processes. What are the opportunities for future therapy of atherosclerosis by epigenetic interventions?
Keywords: Epigenetics; Innate immunity; Macrophage polarization; Inflammation; Histone methylation; Hdac inhibition;

Extracellular vesicles as new pharmacological targets to treat atherosclerosis by Min Yin; Xavier Loyer; Chantal M. Boulanger (90-103).
Extracellular vesicles released by most cell types, include apoptotic bodies (ABs), microvesicles (MVs) and exosomes. They play a crucial role in physiology and pathology, contributing to “cell-to-cell” communication by modifying the phenotype and the function of target cells. Thus, extracellular vesicles participate in the key processes of atherosclerosis from endothelial dysfunction, vascular wall inflammation to vascular remodeling. The purpose of this review is to summarize recent findings on extracellular vesicle formation, structure, release and clearance. We focus on the deleterious and beneficial effects of extracellular vesicles in the development of atherosclerosis. The potential role of extracellular vesicles as biomarkers and pharmacological targets, their innate therapeutic capacity, or their use for novel drug delivery devices in atherosclerotic cardiovascular diseases will also be discussed.
Keywords: Atherosclerosis; Cardiovascular diseases; Pharmacological targets; Extracellular vesicles; Apoptotic bodies; Microvesicles; Exosomes;

Mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease by Sang-Bing Ong; Siavash Beikoghli Kalkhoran; Hector A. Cabrera-Fuentes; Derek J. Hausenloy (104-114).
The past decade has witnessed a number of exciting developments in the field of mitochondrial dynamics – a phenomenon in which changes in mitochondrial shape and movement impact on cellular physiology and pathology. By undergoing fusion and fission, mitochondria are able to change their morphology between elongated interconnected networks and discrete fragmented structures, respectively. The cardiac mitochondria, in particular, have garnered much interest due to their unique spatial arrangement in the adult cardiomyocyte, and the multiple roles they play in cell death and survival. In this article, we review the role of the mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease.
Keywords: Mitochondrial fusion; Mitochondrial fission; MFN1; MFN2; Drp1; OPA1;

Galectin-3 and post-myocardial infarction cardiac remodeling by Wouter C. Meijers; A. Rogier van der Velde; Domingo A. Pascual-Figal; Rudolf A. de Boer (115-121).
This review summarizes the current literature regarding the involvement and the putative role(s) of galectin-3 in post-myocardial infarction cardiac remodeling.Post-myocardial infarction remodeling is characterized by acute loss of myocardium, which leads to structural and biomechanical changes in order to preserve cardiac function. A hallmark herein is fibrosis formation, both in the early and late phase following acute myocardial infarction. Galectin-3, a β-galactoside-binding lectin, which is a shared factor in fibrosis formation in multiple organs, has an established role in cardiac fibrosis in the setting of pressure overload, neuro-endocrine activation and hypertension, but its role in post- myocardial infarction remodeling has received less attention. However, accumulative experimental studies have shown that myocardial galectin-3 expression is upregulated after myocardial infarction, both on mRNA and protein level. This already occurs shortly after myocardial infarction in the infarcted and border zone area, and also at a later stage in the spared myocardium, contributing to tissue repair and fibrosis. This is associated with typical aspects of fibrosis formation, such as apposition of matricellular proteins and increased factors of collagen turnover. Interestingly, myocardial fibrosis in experimental post-myocardial infarction cardiac remodeling could be attenuated by galectin-3 inhibition. In clinical studies, circulating galectin-3 levels have been shown to identify patients at risk for new-onset heart failure and atrial fibrillation. Circulating galectin-3 levels also predict progressive left ventricular dilatation after myocardial infarction.From literature we conclude that galectin-3 is an active player in cardiac remodeling after myocardial infarction. Future studies should focus on the dynamics of galectin-3 activation after myocardial infarction, and study the possibilities to target galectin-3.
Keywords: Galectin-3; Myocardial infarction; Heart failure; Fibrosis; Remodeling; Biomarker;

Wnt signaling in atherosclerosis by W. Matthijs Blankesteijn; Kevin C.M. Hermans (122-130).
Atherosclerosis is a disease of the vascular wall that forms the basis for a large spectrum of pathologies of various organs and tissues. Although massive research efforts in the last decades have yielded valuable information about its underlying molecular mechanisms, this has not led to a translation into effective therapeutic interventions that can stop the progression or even can induce regression of atherosclerosis. This underscores the importance of investigations on the involvement of novel signaling pathways in the development and progression of this condition. In this review we focus on the role of Wnt signaling in atherosclerosis. Experimental evidence is presented that Wnt signaling is involved in many aspects of the development and progression of vascular lesions including endothelial dysfunction, macrophage activation and the proliferation and migration of vascular smooth muscle cells. Subsequently, we will discuss the role of Wnt signaling in myocardial infarction and stroke, two common pathologies resulting from the progression of atherosclerotic lesions towards an unstable phenotype. Despite the fact that the published data sometimes are ambiguous or even conflicting, a picture is emerging that an attenuation of Wnt signaling is beneficial for the cardiovascular system that is compromised by atherosclerosis.
Keywords: Wnt; Frizzled; Signal transduction; Atherosclerosis; Myocardial infarction; Stroke;

The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review summarizes the evidence for this link between cardiovascular disease and late onset Alzheimer dementia. Only evidence from human research is considered here. Longitudinal studies show an association between high blood pressure and pathological accumulation of the protein amyloid-beta42, and an even stronger association between vascular stiffness and amyloid accumulation, in elderly subjects. Amyloid-beta42 accumulation is considered to be an early marker of Alzheimer disease, and increases the risk of subsequent cognitive decline and development of dementia. These observations could provide an explanation for recent observations of reduced dementia prevalence associated with improved cardiovascular care.
Keywords: Cognitive impairment; Dementia; Cerebral blood flow; Cardiovascular disease;