Current Vascular Pharmacology - Volume 15, Issue 6, 2017

Background: Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels. This physiological process is a hallmark event in normal embryonic development as blood vessels generally supply both oxygen and nutrients to the cells of the body. Any disruption in this process can lead to the development of various chronic diseases, including cancer. In cancer, aberrant angiogenesis plays a prominent role in maintaining sustained tumor growth to malignant phenotypes and promoting metastasis. The leakiness in the tumor microvasculature is attributed to the tumor cells migrating to distal site organs and forming colonies. Methods: In this article, we briefly review the various mediators involved in the angiogenic process and the anti-angiogenic potential of selected natural compounds against various malignancies. Results: Several growth factors and their receptors such as vascular endothelial growth factor and receptor (VEGF/VEGFR), basic fibroblast growth factor and receptor (bFGF/FGFR), angiopoietins, and hypoxia inducible factors facilitate the development of angiogenesis and are attractive anti-cancer targets. Natural products represent a rich diversity of compounds for drug discovery and are currently being actively exploited to target tumor angiogenesis. Conclusion: Agents such as curcumin, artemisinin, EGCG, resveratrol, emodin, celastrol, thymoquinone and tocotrienols all have shown prominent anti-angiogenic effects in the preclinical models of tumor angiogenesis. Several semi-synthetic derivatives and novel nano-formulations of these natural compounds have also exhibited excellent anti-angiogenic activity by increasing bioavailability and delivering the drugs to the sites of tumor angiogenesis.

Background: Many studies have shown that the reduction of low density lipoprotein (LDLC) levels provides cardiovascular protection; therefore LDL-C is considered to be a core therapeutic target in anti-hyperlipidaemia treatment. However, the LDL-C goal attainment is often not satisfied in China with conventional lipid-lowering agents. Many patients seek help from Chinese Herbal Medicine (CHM). To further understand the current use of CHM in hyperlipidaemia, we conducted a review based on a systematic literature search and data mining. Methods: We comprehensively searched MEDLINE, EBSCO, Cochrane Library, EMBASE, Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI) and Wanfang database to identify potentially relevant articles. We included literatures that met the following criteria: (1) randomized or non-randomized controlled trials; (2) observational clinical trials; (3) case series or case reports. In order to enrich the systematic literature searching and provide the quantitative relationship between relative items and the treatment of hyperlipidaemia, the data mining was also conducted by filtering the biomedical literature on hyperlipidaemia in SinoMed and other available databases like VIP and CNKI. Results: In summary, 282 records of CHM on hyperlipidaemia were captured and analysed. The top used single herb was Radix Salviae Miltiorrhizae. The most frequently used formula was Xuefuzhuyu Decoction. The most used herbs in clinical practice have some pharmacological evidences. The mechanisms are different, but could be classified into three categories: inhibiting synthesis, increasing decomposition and reducing absorption. Conclusion: CHM shows positive effect in the treatment of hyperlipidaemia and has the potential to be used in combination with conventional drugs. However, their use should be demonstrated in highquality clinical trials and clinicians should pay attention to potential herb-drug interactions.

Background: Leaves of Ginkgo biloba, a “living fossil,” have been used as traditional herbal medicine for hundreds of years in China. Currently, its application in vascular protection is garnering much attention. Methods: In this manuscript, preclinical studies were reviewed to discuss various mechanisms underlying the vascular protection by Ginkgo biloba extract (GBE). Additionally, we reviewed clinical studies to present the application of GBE in the ischaemic disease. Results: GBE, a commonly used dietary supplement, has been shown to act as an antioxidant and freeradical scavenger, a membrane stabilizer, an inhibitor of the platelet-activating factor, a vasodilator, and a regulator of metabolism. Currently, there exist a growing number of clinical studies about GBE in the application of cardiovascular disease, peripheral vascular disease (PVD) and diabetic vascular complications. Conclusion: GBE, a promising therapeutic agent for cardiovascular and ischaemic diseases, exerts vascular- protection function by a comprehensive mechanisms.

Background: Evidence of ginseng for reducing blood pressure (BP) in hypertensive patients is controversial. This systematic review updated the previous reviews and evidence for it. Methods: Ten databases were searched from their inception through October 2016, without language restriction. Randomized clinical trials (RCTs) were included if any types of ginseng were tested as the sole treatment or as an adjunct to other treatments for pre-hypertension or hypertension. The risk of bias (ROB) was assessed with Cochrane ROB tools by two independent reviewers. Results: We found 528 potentially relevant articles, of which 9 RCTs met our inclusion criteria. Two studies reported positive effects of Korean red ginseng (KRG) on acute reduction of systolic BP (SBP: n=54, mean differences (MD), -6.52; P=0.0002; I2=0%) and diastolic BP DBP: MD, -5.21; P=0.0001; I2=0%), while two other trials failed to do so with north American ginseng (NAG) in both SBP and DBP. Five RCTs assessed the long-term effects of ginseng (KRG or NAG) on SBP and DBP. Two studies showed positive effects of KRG on reducing SBP and DBP compared with placebo (SBP: n = 183, MD, -2.92, P=0.04; I2 = 0%; DBP: MD, -3.19, P=0.008; I2 = 0%). Conclusion: This systematic review provides positive evidence for the efficacy of KRG on reducing blood pressure in patients with pre-hypertension and hypertension in acute and long-term. Future RCTs appear to be warranted.

Background: Matrix metalloproteinases (MMPs) are zinc-dependent proteases that degrade components of the extracellular matrix (ECM). In glomerular disease, MMPs are major regulators of ECM degradation as well as structural and functional integrity in the glomerulus. In altered matrix composition diseases, glomerular damage is due to increased degradation of kidney and vessel basement membranes (BMs) by MMPs. MMP -2 and -9 are both considered as the main enzymes that degrade collagen type-IV (coll-IV), which represents the key collagenous component of ECM and constitutes the architectural structure of vessels and glomerular BM. here is growing evidence implicating MMPs in atherosclerosis as well as in cardiovascular disease (CVD) and chronic kidney disease (CKD). Specific endogenous tissue inhibitors of MMPs (TIMPs) are also implicated in CKD, CVD and diabetic nephropathy (DN). Conclusion: The present review discusses the role of MMPs -2 and -9 in DN, as a leading cause of endstage renal disease and as a model of the link between progressive glomerulosclerosis and MMP expression.

Background: Patients with diabetes usually exhibit diabetic dyslipidaemia. Aim: The aim of the review is to present the quantitative and qualitative alterations of lipids and lipoproteins and the associated mechanisms in patients with diabetic dyslipidaemia. Results: The main quantitative changes observed in patients with diabetic dyslipidaemia are increased triglycerides and decreased high-density lipoprotein (HDL) cholesterol levels. Qualitative abnormalities mainly include increased small dense low-density lipoprotein (LDL) particles (despite similar serum LDL cholesterol levels as non-diabetic subjects) and alterations in the apolipoprotein content of HDL particles. Alterations in the activities of enzymes involved in lipoprotein metabolism, such as cholesteryl ester transfer protein, and the lipoprotein content of lipid particles, along with their glycation and oxidation, play a role in the pathogenesis of diabetic dyslipidaemia. Conclusion: Diabetic dyslipidaemia is associated with quantitative and qualitative alterations of lipids and lipoproteins, which are associated with increased cardiovascular risk.

Purpose: Patients undergoing cardiac surgery with extracorporeal circulation (ECC) frequently present haemorrhages as a complication associated with high morbidity and mortality. One of the factors that influences this risk is the volume of blood infused during surgery. The objective of this study was to determine the optimal volume of autologous blood that can be processed during cardiac surgery with ECC. We also determined the number of salvaged red blood cells to be reinfused into the patient in order to minimize the risk of haemorrhage in the postoperative period. Methods: This was an observational retrospective cross-sectional study performed in 162 ECC cardiac surgery patients. Data regarding the sociodemographic profiles of the patients, their pathologies and surgical treatments, and the blood volume recovered, processed, and reinfused after cell salvage were collected. We also evaluated the occurrence of postoperative haemorrhage. Results: The volume of blood infused after cell salvage had a statistically significant effect (p < 0.01) on the risk of post-operative haemorrhage; the receiver operating characteristic sensitivity was 0.813 and the optimal blood volume cut-off was 1800 ml. The best clinical outcome (16.7% of patients presenting haemorrhages) was in patients that had received less than 1800 ml of recovered and processed autologous blood, which represented a volume of up to 580 ml reinfused red blood cells. Conclusion: The optimum thresholds for autologous processed blood and red blood cells reinfused into the patient were 1800 and 580 ml, respectively. Increasing these thresholds augmented the risk of haemorrhage as an immediate postoperative period complication.

Objective: Treatment of wounds difficult to heal concerns 50% of the elderly population in Italy and is therefore a relevant social burden. The present study shows how the treatment with autologous leuco-platelets reduces the healing time of wounds improving the functional recovery. Patients and Methods: Patients (n=100) with ulcers of the legs were divided in two groups: 1) 50 patients treated with conventional therapies; 2) 50 patients treated with autologous leuco-platelet concentrate (LPC) and hyaluronic acid (HIAFF, Hyalofill-F® ) as a scaffold. Results: After 2 months, a 49% reduction in wound area was observed in the second group and in about 65% wound reduction was achieved in 15 days (4 LPC dressings). In contrast, patients treated by conventional therapies, showed a longer healing time and a greater percentage of failures. Morphometric analysis of biopsy samples obtained from the edge as well as from the bottom of the lesions obtained from the LPC group, detected an abundant presence of neoformed capillaries, characterized by a cubic, "reactive endothelium", close to the site of LPC infiltration. Conclusion: These results suggest that healing was promoted not only by limiting bacterial infections but also by the release of chemotactic and proangiogenic factors from leukocytes and platelets, improving the neoformation of capillaries.

Background: Sugen5416 (semaxinib) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor. A rat model of Pulmonary Arterial Hypertension (PAH), created with Sugen5416 and chronic hypoxia, is known to have similar histological findings to those of PAH patients. Objective: To evaluate the pathophysiological mechanisms of cardiac remodeling due to hypoxic stress with Sugen5416 in vivo. Methods: Male Sprague-Dawley rats were exposed to hypoxia (10 ± 1% O2) for 2 weeks after a single injection of Sugen5416 (SU-hypoxia group) or the vehicle (V-hypoxia group). Results: Hypoxia elevated right ventricular (RV) systolic pressure and caused RV remodeling on Day 14. By electron microscopy, metamorphosis of capillaries with endothelial cell occlusive degeneration was observed in the RV myocardium of the SU-hypoxia group from Day 3. After reoxygenation, progressive RV remodeling with extensive degeneration of cardiomyocytes was observed in the SUhypoxia group, associated with a significant increase of oxidative stress and TUNEL-positive cells in both RV and left ventricular myocardium on Day 84. The expression of VEGF mRNA in the RV myocardium was significantly suppressed in the SU-hypoxia group on Day 3, whereas delayed activation of VEGF/extracellular signal-regulated kinase (ERK) signaling pathway on Day 14 were observed. Conclusion: Capillary degeneration and activation of VEGF/ERK signaling pathway might be crucial to accelerate the cardiac remodeling due to hypoxic stress with Sugen5416.

Background: Add-on therapy with the Mineralocorticoid-Receptor-Antagonists (MRAs) spironolactone and eplerenone was shown to enhance the cardioprotective action of angiotensinconverting- enzyme-inhibitors (ACEIs), angiotensin-receptor-blockers (ARBs) and/or β-blockers in nondialysis patients with congestive heart failure (CHF) and reduced left ventricular (LV) ejection fraction. The risk/benefit ratio of MRAs in dialysis patients is less well defined, owing to concerns that their cardioprotective actions may be counteracted by excess risk of hyperkalemia. Methods: We performed a systematic literature search of MEDLINE/PubMed database (inception to September 15, 2016) to identify randomized controlled studies evaluating the effects of spironolactone and eplerenone on surrogate cardiovascular risk factors and clinical outcomes in patients receiving hemodialysis or peritoneal dialysis. Results: A growing body of evidence derived from small randomized studies suggests that MRA therapy improves a number of surrogate cardiovascular risk factors (i.e. blood pressure, LV mass index, LV ejection fraction, carotid intima-media-thickness) in long-term dialysis patients. Two larger studies evaluating “hard” cardiovascular endpoints showed that these cardioprotective actions of MRAs are translated into a clinically relevant (up to 60%) reduction in the risk of all-cause and cardiovascular mortality. On the other hand, MRA use was shown to be accompanied by a parallel increase in the risk of hyperkalemia and gynecomastia. Conclusion: Small, hypothesis-generating randomized trials support a cardioprotective role of MRA therapy in patients receiving hemodialysis or peritoneal dialysis. These promising results call for larger, properly-designed studies aiming to fully elucidate the potential harms and benefits of MRAs in this high-risk population. In anticipation of the results of ongoing outcome trials, the wide use of MRAs in dialysis patients should be avoided.