Current Pharmaceutical Design - Volume 23, Issue 10, 2017

Background: Nitric oxide (NO) is a potential biochemical, cardio-metabolic risk marker. The production of NO is catalyzed by different isoforms of enzymes, NO synthases (NOS). An altered NO level is associated with obesity, insulin resistance (IR), diabetes and cardiovascular diseases (CVD). Activity of NOS and NO production are regulated by various hormones under physiological and pathophysiological condition. Methods: Data used for this review were obtained by searching the electronic database [PUBMED/MEDLINE 1984 - May 2016]. Additionally, abstracts from national and international diabetes and cardiovascular related meetings were searched. The main data search terms were: nitric oxide, nitric oxide synthase, cardio-metabolic risk, obesity, diabetes, cardiovascular disease, estradiol and insulin-like growth factor-1. Results: In this review, we summarize the recent literature data related to the regulation of endothelial NOS (eNOS), inducible (iNOS) activity/expression, and thereby NO production by the hormones: estradiol (E2), and insulin-like growth factor-1 (IGF-1). Conclusion: Understanding the regulation of NO production by different hormones such as E2, and IGF-1 may provide novel and useful knowledge regarding how endothelial dysfunction (ED) is linked with cardio-metabolic alterations and diseases.

Background: Endothelial dysfunction (ED) is a pathophysiological mechanism present in patients affected by type 2 diabetes (T2DM) supporting the development of cardiovascular disease. Among immune- and inflammatory cells accelerating atherosclerosis, dendritic cells (DC) play a pivotal role, however their pathogenetic mechanism has not been fully clarified, at present. The aim of our review is to explore the relationship between ED, DCs and cardiovascular events. Methods: We analysed the literature in Medline database under ‘endothelial function OR dysfunction OR vasodilatation’ AND ‘dendritic cells” OR “innate immunity” OR “adaptive immunity” AND “diabetes” AND “cardiovascular disease” OR “atherosclerosis”. Research articles, systematic reviews and clinical trials have been screened. Results: Both conventional DCs (cDCs) and plasmacytoid cells (pDCs) have been found in the atherosclerotic lesions, together with other pro-inflammatory cells, leading to increase local inflammation. This inflammatory state drives DC interaction with dysfunctional endothelium activating vascular smooth muscle cells. Clinical studies have reported a dysregulation in circulating DC number and function in T2DM patients, especially in those with macrovascular complications, and a significant correlation between reduction in pDCs, TNF-α production and poor glycemic control has been reported. Conclusion: Several studies have proven the prognostic significance of endothelial function and the accumulation of cDCs and pDCs in the arterial intima, thus suggesting their pathogenetic role in atherogenesis. A lack of clinical results is evident, since most observations on human studies are based on circulating measurements despite the fact that different DCs, residing in different tissues, were not detectable in peripheral blood samples. Further preclinical and clinical studies are needed, which should include the measurement of both circulating and tissueresiding DCs simultaneously.

Background: Residual cardiovascular risk (RCVR) is an emerging issue in the clinical and therapeutic management of patients affected by hypertension. In fact, a number of clinical studies showed that even in case of optimal blood pressure (BP) control, the hypertensive patients still carry a sizeable increase in the CV risk as compared to normotensive individuals. Methods: We will review the clinical evidence about the determinants and the impact of RCVR on hypertension, with a specific focus on the progression of vascular damage. Results: The presence of RCVR in hypertensive patients is a significant phenomenon which challenges our clinical effort far beyond the reaching of BP targets. Although major determinants of RCVR are still undefined, there is a clear indication about the importance of an early and sustained control of BP values, so as to prevent the onset of target organ damage. In fact, our data and findings from the literature indicate that the 'pseudo-normalization" of BP is not sufficient to abolish the risk of pro-atherogenic remodeling of arterial vessels. Conclusion: Additional studies are needed to establish whether the intervention on specific BP profiles and inflammatory mechanisms can have some clinical relevance in the management of RCVR. In the meanwhile, the precise phenotyping of the CV risk profile of each patient, coupled with a tailored pharmacological approach, represents the most effective strategy to hinder the progression of vascular damage and reduce the RCVR.

Background: Metabolic homeostasis is achieved by proper functioning of a complex endocrine milieu, comprising of signals arising from the brain and peripheral tissues. Our knowledge of the factors regulating such balance is rapidly evolving, as new signaling molecules are being characterized. Of central interest is nesfatin-1, owing to its multifunctional tissue specific actions regulating food intake, body weight, blood glucose and cardiac functions. Method: This review discusses the tissue/system wide distribution and actions of nesfatin-1 in regulating metabolic and cardiovascular functions in healthy conditions and diseases. Results: Nesfatin-1 is an 82 amino acid peptide encoded in the secreted precursor, nucleobinin-2 (NUCB2). It was first reported as a novel anorexigen and a fat reducing orphan ligand. Research to date has established nesfatin-1 in the regulation of food intake via modulation of neuropeptides in the feeding centers of brain. Nesfatin-1 expression was also reported to have a spectrum of peripheral tissue specific actions, which includes insulin secretion (pancreas), fat and glucose modulation (adipocyte), gastric motility and gastric acid secretion (stomach), hormone secretion and transit time (intestine) and mean arterial pressure and cardiac injury (heart). Abnormal levels of nesfatin-1 in circulation and/or variations in tissue specific expression have been observed in obesity, diabetes and cardiovascular diseases. Conclusion: The multifunctional biological actions of nesfatin-1 propelled this peptide as a therapeutic target, and as a potential biomarker of diseases. However, a better and comprehensive understanding of tissue specific effects of nesfatin-1 is critical prior to exploring its possible use in the detection and treatment of diseases.

Background: Nuclear factor-erythroid related factor-2 (Nrf2) is a master regulator of transcriptional activation of anti-oxidants in cells. Similarly, heme oxygenase (HO) is a cytoprotective protein with anti-oxidant effects. This review article will shed more light on the interaction between Nrf2 and HO. Methods and Results: A PubMed search was done for recent articles on Nrf2 and HO. These studies suggested that under normal physiological conditions, Nrf2 is bound within the cytoplasm to its repressor, Kelch-like ECHassociated protein (Keap1), an oxidative stress sensor. Upon activation, Nrf2 translocates to the nucleus and binds to the antioxidant-response-element located at the promoter region of some anti-oxidants including the cytoprotective protein HO. Since the HO-1 gene harbors binding site for Nrf2, mutual stimulatory and regulatory effects between Nrf2 and HO-1 have been reported. Accordingly, the interaction between Nrf2 and HO-1 has been implicated in the regulation of many physiological anti-oxidants including superoxide dismutases, catalase, glutathione S-transferase, peroxidase, NAD(P)H quinone oxidoreductase, and thioredoxin. Conclusion: Although an overwhelming body of evidence has underscored unique anti-oxidant attributes of HO- 1 and Nrf2, emerging evidence suggests that the cytoprotective activities of Nrf2 and HO-1 may be attributed, at least in part, to the potentiation of different anti-oxidants in physiological mileu. Since Nrf2 binds to the antioxidant responsive element of HO-1, the coordinated regulation of Nrf2 and keap1 by the HO-system may constitute the basis of many physiological effects of HO-1 including its effects against oxidative stress and inflammation in a wide spectrum of cardiovascular, cardio-metabolic and other related diseases.

Background: Among individuals with Type 2 diabetes (T2DM), cardiovascular disease (CVD) is the leading cause of morbidity and mortality. Sex and gender differences (SGDs) in the cardiovascular consequences of T2DM are relevant suggesting the need for a more aggressive CVD preventive strategy in diabetic women as they lose the so-called "female advantage" in terms of CVD risk comparing with the nondiabetic population. Multiple factors may explain the disproportion in CVD risk among women with diabetes comparing with diabetic men or non-diabetic women. Both genetic and hormonal factors only partially explain SGDs in CVD risk in diabetes. However, women likely reach diagnosis later and in worse conditions, they undergo both diagnostic and therapeutic supports in lower percentage and, finally, they are not able to obtain therapeutic goals recommended by guidelines. Concerning the cardiovascular system, diabetes amplifies the extent of damage at both micro- and macrovascular level differently among sexes. Methods: The aim of this review is to clarify, in a sex and gender perspective, the impact of diabetes in CVD risk and to summarize the most important SGDs in CVD primary and secondary prevention strategies such as antiplatelet drugs and statins. Results: The efficacy of ASA and/or statins in secondary prevention is documented in both sexes independently by the presence of T2DM. A different approach to CVD primary prevention with ASA using the age cut-off to discriminate sex differences has been recommended. The use of statins for primary prevention in women should be accurately monitored for the occurrence of myalgia and risk of developing diabetes. Conclusion: A gender approach in CVD prevention strategies is urgently required to achieve a sensible reduction of adverse CV events.

Background: Statins remain the cornerstone of hypolipidaemic drug treatment. However, statins exert adverse effects on glucose metabolism. Given that new onset diabetes mellitus (NODM) and worsening of glucose control in patients with established type 2 diabetes mellitus (T2DM) is related to low density lipoprotein cholesterol (LDL-C) reduction, it would be of great interest to investigate if this is also the case for proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, which have recently be licensed for the treatment of hypercholesterolaemia. Methods: We reviewed the published papers on the relation between circulating PCSK9 and diabetogenesis. Results: Recent data suggest that increased circulating PCSK9 levels, besides causing dyslipidaemia, are related to increased glucose levels, metabolic syndrome, and even T2DM. On the contrary, fasting plasma glucose and HbA1c levels are not adversely affected during treatment with human antibodies against PCSK9 in patients at low risk for T2DM, in patients at high risk of T2DM and in patients with established T2DM. Plasma lipoproteins (mainly LDL-C reduction) are similarly affected in patients with or without T2DM, and recent data suggest that PCSK9 inhibition might reduce cardiovascular events in patients with T2DM at least as much as in those without T2DM. Conclusion: The use of PCSK9 inhibitors appears to be related to a substantial clinical benefit without adversely affecting glucose metabolism and without increasing the incidence of NODM. Large ongoing studies will have to confirm these findings before expanding the use of these agents.

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomal degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation which in turn leads to an increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDLC metabolism has been discovered in 2003 there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those the fully human anti-PCSK9 antibodies alirocumab and evolocumab have been studied in a wide range of patients such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia and have been shown to decrease LDL-C overall by ~50-70%. Rates of achieving LDL-C goals, depending on individual risk, are up to 87 -98% of treated subjects. Multiple phase III studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016 and 2017 for evolocumab and alirocumab, respectively. In 2015 both alirocumab and evolocumab were approved for the treatment of hypercholesterolemia in the European Union and in the US. Preliminary data show an improvement in cardiovascular morbidity and mortality by ~50%. If the large ongoing endpoint trials confirm the cardiovascular efficacy and overall safety of these drugs, PCSK9 antibodies will revolutionarize lipid-lowering therapy.

Background: Treatment with statins substantially reduces cardiovascular morbidity and mortality both in patients with and without established cardiovascular disease. Accordingly, statins represent the cornerstone of lipid-lowering treatment. However, there are still unmet clinical needs in the management of dyslipidemia. Indeed, it is difficult to achieve low-density lipoprotein cholesterol (LDL-C) targets in many patients, particularly in those at very high cardiovascular risk or in those with very high baseline LDL-C levels [e.g. with heterozygous familial hypercholesterolemia (FH)]. Moreover, a sizable proportion of patients are not able to tolerate high doses of statins, mostly due to muscle-related adverse effects. In these patient populations, inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) with monoclonal antibodies appears to represent a useful tool for achieving LDL-C targets. Methods: In the present review, we summarize the current knowledge on the effects of the PCSK9 inhibitors alirocumab and evolocumab on lipid levels in various populations and discuss the role of these agents in the management of dyslipidemia. Results: In addition to a substantial reduction in LDL-C levels (by 50-60%), PCSK9 inhibitors also lower triglyceride, non-high-density lipoprotein cholesterol (non-HDL-C) and lipoprotein (a) levels and increase HDL-C levels. Preliminary data suggest that PCSK9 inhibitors are safe. However, ongoing randomized, placebo-controlled trials will provide definitive evidence on the safety of these novel agents and on their effects on cardiovascular morbidity and mortality. Conclusion: Given the high cost of PCSK9 inhibitors, their use should be restricted to carefully selected, veryhigh risk patients until the results of these trials are available.

Background: Most proteoglycans are heterogeneous molecules composed of a protein core with glycosaminoglycans (GAGs) attached. GAGs are highly negatively charged molecules that readily bind to enzymes, growth factors, cytokines etc. and as such have many functions. The role played by proteoglycans in diabetes has only recently been investigated. Methods: The importance of proteoglycans and the effects of diabetes on proteoglycans are discussed. Possible strategies for reducing diabetic complications associated with preventing proteoglycan destruction are examined. Results: Proteoglycans are altered in the endothelium, vascular wall, kidney, retina, heart, gut epithelial cells, bone and cartilage with diabetes. A decrease in proteoglycans, associated with hyperglycemic conditions, is reported to be due to a decrease in proteoglycan synthesis or an increase in destruction. Destruction may be a result of an upregulation of enzymes that degrade GAGs or destruction by reactive oxygen species. Several studies suggest that upregulation of heparanase and its destruction of heparan sulfate proteoglycans may be responsible for many of the complications associated with diabetes particularly in the kidney and blood vessels leading to chronic kidney disease, atherosclerosis and acute coronary syndrome. Preliminary studies suggest that administration of GAGs may be beneficial in reducing or delaying the harmful consequences of diabetes in the kidney and retina. Conclusions: Changes in proteoglycans are partially responsible for diabetic complications. Recent studies demonstrate that administration of GAGs may reduce or delay diabetic complications. Further studies are required to understand the alterations in proteoglycans associated with diabetes, and the protective potential of administered GAGs.

Background: Diabetes mellitus is a major cardiovascular risk factor. Despite the vast pharmaceutical armamentarium, current therapeutic options for the treatment of type 2 diabetes mellitus were unable to provide consistent cardiovascular benefits, apart for metformin. The newest antidiabetic class of drugs, the SGLT-2 inhibitors, seem to provide significant survival benefits. The aim of this review is to present available data that will clarify whether SGLT-2 inhibitors could precipitate in reducing cardiovascular risk in diabetes mellitus. Methods: A comprehensive literature search was performed to identify available data from clinical and experimental studies evaluating the impact of SGLT-2 inhibitors in cardiovascular risk factors and outcomes. Results: Along with a mild antihyperglycemic effect, SGLT-2 inhibitors seem to possess multi-dimensional properties, affecting positively several recognized cardiovascular risk factors such as increased blood pressure, arterial stiffness, body weight and dyslipidemia. Furthermore, preliminary data point towards additional benefits, including reduction of albuminuria in diabetic nephropathy, and reduction of oxidative markers and fatty liver disease in experimental models. The efficacy and safety profile of empagliflozin, an SGLT-2 inhibitor, was evaluated in the EMPA-REG outcome study, and the results were quite impressive. Further credence comes from the analysis of pooled data of SGLT-2 inhibitors trials that have shown similar results. Conclusion: SGLT-2 Inhibitors seem to be related with ameliorating effects on multiple cardiovascular risk factors. The first data from the EMPA-REG outcome study are indeed very promising. Several ongoing cardiovascular studies with this novel class of drugs will shed light and enforce or question current enthusiasm.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control without promoting hypoglycemia in the absence of exogenously administered insulin. Methods: The present narrative review addresses the putative associations between SGLT2i and several cardiovascular (CV) and microvascular risk factors, as well as their effects on cardiac and renal function. Results: SGLT2i improve several CV risk factors, including fasting and postprandial plasma glucose levels, lipids, blood pressure, body weight, serum uric acid and arterial stiffness. These drugs may also favorably modulate cardiac and renal function via their effects on inflammation, oxidative stress, diuresis, fluid and sodium retention, myocardial function, vascular resistance and ‘fuel’ metabolism. In the EMPA-REG OUTCOME study, the first published large CV outcome SGLT2i trial, empagliflozin significantly reduced the primary composite outcome (i.e. CV death, nonfatal myocardial infarction or stroke) and all-cause death as well as hospitalization for heart failure. In addition, empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in patients at high CV risk. Conclusion: Multiple metabolic benefits may account for the positive clinical outcomes in the EMPA-REG OUTCOME study. Ongoing CV outcome trials involving other SGLT2i will help establish whether the reported CV and microvascular risk benefits are compound-specific or drug class effects.

Background: Progranulin is a multifunctional regulatory protein with growth-promoting, neuroprotective and antiinflammatory activities. Recent studies indicate that progranulin is one of the adipose tissue hormones (adipokines). Progranulin expression in visceral adipose tissue and circulating progranulin concentration are increased in obesity and hyperprogranulinemia is involved in the pathogenesis of obesity-associated insulin resistance. Progranulin impairs insulin signaling and reduces insulin-induced glucose uptake both in vitro and in vivo whereas progranulin deficiency protects from high fat diet-induced insulin resistance. Several studies, including some prospective ones, have demonstrated the association between high progranulin and type 2 diabetes and its complications such as nephro- and retinopathy as well as non-alcoholic fatty liver disease. It is quite well established that progranulin contributes to insulin resistance and resulting deterioration of carbohydrate metabolism. In addition, progranulin may be associated with the development of diabetic microangiopathy, fatty liver disease and possibly with the increased risk of cancer in subjects with the metabolic syndrome. On the other hand, progranulin augments vasorelaxation, inhibits inflammatory reaction, is neuroprotective and reduces ischemiareperfusion injury. Conclusion: Progranulin has both detrimental and beneficial effects. More clinical studies including prospective ones are needed to clarify the role of progranulin in obesity-associated pathologies such as diabetes, hyperlipidemia, hypertension and atherosclerosis.

Backgound: Current drug therapy for the management of arterial hypertension and heart failure has provided substantial benefits but has also some limitations. LCZ696, a dual inhibitor of angiotensin receptor blockers and neprilysin, and finerenone, a non-steroidal mineralocorticoid receptor antagonist, are two recently developed novel agents for the management of these conditions. Methods: This review aims to present the pathophysiological basis for the use of these two novel drugs, critically discuss available clinical data, and provide future perspectives. Results: LCZ696 seems a very promising antihypertensive agent, that additionally generates clinically meaningful benefits in patients with heart failure with reduced injection fraction and raises expectations for the management of patients with heart failure with preserved ejection fraction. Finerenone aims to be safer than current aldosterone antagonists and has been so far tested in patients with heart failure and in patients with albuminuria. First available data are very promising for the efficacy of the drug, while it provides a better safety profile than current mineralocorticoid antagonists. Conclusion: LCZ696 and finerenone are two novel drugs for the management of arterial hypertension and heart failure. First available data point toward important clinical benefits from their use. Future large trials further investigating the cardiovascular profile of these agents will establish the use of these drugs.

Background: The sodium/potassium- adenosine- triphosphatase (Na+/K+-ATPase) is an important mediator in vasculature tone and contractility, and its abnormal regulation has been implicated in many diseases such as obesity, insulin resistance, diabetes, and hypertension. Decreased Na+/K+-ATPase abundance and its altered isoform expression induce cardiomyocytes death and cardiac dysfunction, possibly leading to the development of myocardial dilation and heart failure. Therefore, the regulation of Na+/K+-ATPase activity/expression could be important in treatment and possible prevention of cardio-metabolic diseases. A number of hormones and environmental factors regulate the function of Na+/K+-ATPase in response to changing cellular requirements. Estradiol and insulin like growth factor-1 (IGF-1) are among potent hormones that positively regulate Na+/K+- ATPase activity or de novo synthesis of &α - and β - subunits. Both estradiol and IGF-1 have a huge therapeutic potential in treatment of vasculopathy in cardio-metabolic diseases. Methods: We searched the MEDLINE and PUBMED databases for all English and non-English articles with an English abstract from April 1978 to May 2016. The main data search terms were: Na+/K+-ATPase; estradiol and Na+/K+-ATPase; estradiol, Na+/K+-ATPase and CVS; estradiol, Na+/K+-ATPase and CVD; estradiol, Na+/K+- ATPase and obesity; estradiol, Na+/K+-ATPase and diabetes; estradiol, Na+/K+-ATPase and hypertension; IGF-1; IGF-1 and Na+/K+-ATPase; IGF-1, Na+/K+-ATPase and CVS; IGF-1, Na+/K+-ATPase and CVD; IGF-1, Na+/K+- ATPase and obesity; IGF-1, Na+/K+-ATPase and diabetes; IGF-1, Na+/K+-ATPase and hypertension. Results: The present review discusses the latest data from animal and human studies which focus on the effects of estradiol and IGF-1 on Na+/K+-ATPase regulation in physiological and pathophysiological conditions in cardiovascular system. Conclusion: Understanding the molecular mechanisms of estradiol and IGF-1 action on Na+/K+-ATPase in humans, may help resolving outstanding issues and developing new strategies for the protection and treatment of cardiovascular diseases.

Background: Lipoprotein(a) [Lp(a)] is a particle similar to LDL that contains an additional protein called apolipoprotein(a) [apo(a)]. Recent epidemiologic and Mendelian randomization studies have provided evidence that Lp(a) may be causally related to the pathogenesis of atherosclerosis and cardiovascular disease (CVD). While the risk association between Lp(a) concentrations and CVD is weak it seems to be continuous in shape and without an obvious threshold for Lp(a) levels. Methods: Circulating concentrations of Lp(a) are genetically determined and desirable levels are < 50 mg/dl. A plasma concentration of 60 mg/dl is associated with an odds ratio for coronary heart disease of about 1.5 after adjustment for other cardiovascular risk factors. Results: Extended-release niacin is the pharmacologic means of choice for decreasing elevated Lp(a) levels by ~20-30% but it is often poorly tolerated due to adverse reactions. Diet, exercise and lipid-lowering drugs such as statins, fibrates and ezetimibe are without effect. In patients with severe progressive CVD and very high Lp(a) levels, lipoprotein apheresis may be used to decrease Lp(a) concentrations. However, it is an expensive and impractical treatment for most patients and its feasibility depends on the healthcare reimbursement system of the respective country. Since no established treatment reduces Lp(a) without influencing other lipoproteins, there has been no trial examining whether decreasing Lp(a) concentrations translates to clinical benefits. Conclusion: Recently, an antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, has been shown to selectively decrease Lp(a) by ~80%. A phase 2 study with this drug has been completed in late 2015 and results are expected to be published soon.