Sanja Soskic

Regulation of Inducible Nitric Oxide Synthase (iNOS) and its Potential Role in Insulin Resistance, Diabetes and Heart Failure.

Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. NO is a reactive oxygen species as well as a reactive nitrogen species. It is a free radical which mediates several biological effects. It is clear that the generation and actions of NO under physiological and pathophysiological conditions are regulated and extend to almost every cell type and function within the circulation. In mammals 3 distinct isoforms of NOS have been identified: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The important isoform in the regulation of insulin resistance (IR) is iNOS. Understanding the molecular mechanisms regulating the iNOS pathway in normal and hyperglycemic conditions would help to explain some of vascular abnormalities observed in type 2 diabetes mellitus (T2DM). Previous studies have reported increased myocardial iNOS activity and expression in heart failure (HF). This review considers the recent animal studies which focus on the understanding of regulation of iNOS activity/expression and the role of iNOS agonists as potential therapeutic agents in treatment of IR, T2DM and HF.

Peroxisome Proliferator-Activated Receptors and Atherosclerosis

The peroxisome proliferator-activated receptors (PPARs) represent the family of 3 nuclear receptor isoforms-PPARα, -γ, and -δ/β, which are encoded by different genes. As lipid sensors, they are primarily involved in regulation of lipid metabolism and subsequently in inflammation and atherosclerosis. Atherosclerosis considers accumulation of the cells and extracellular matrix in the vessel wall leading to the formation of atherosclerotic plaque, atherothrombosis, and other vascular complications. Besides existence of natural ligands for PPARs, their more potent synthetic ligands are fibrates and thiazolidindiones. Future investigations should now focus on the mechanisms of PPARs activation, which might present new approaches involved in the antiatherosclerotic effects revealed in this review. In addition, in this review we are presenting latest data from recent performed clinical studies which have focus on novel approach to PPARs agonists as potential therapeutic agents in the treatment of complex disease such as atherosclerosis.

Obesity and vitamin D deficiency: trends to promote a more proatherogenic cardiometabolic risk profile.

Vitamin D deficiency is associated with cardiometabolic risk factors (eg, hypertension, insulin resistance, type 2 diabetes mellitus, obesity, and dyslipidemia). We studied 50 obese patients (body mass index [BMI]: 43.5 ± 9.2 kg/m2) and 36 normal weight participants (BMI: 22.6 ± 1.9 kg/m2). The prevalence of vitamin D deficiency (25-hydroxyvitamin D, 25(OH)D < 50 nmol/L) was 88% among obese patients and 31% among nonobese individuals; 25(OH)D levels were lower in the obese group (27.3 ± 13.7 vs 64.6 ± 21.3 nmol/L; P < .001). There was a negative correlation between vitamin D level and anthropometric indicators of obesity: BMI (r = −0.64; P < .001), waist circumference (r = −0.59; P < .001), and body fat percentage (r = −0.64; P < .001) as well as with fasting plasma insulin (r = −0.35; P < .001) and homeostasis model assessment of insulin resistance (r = −0.35; P < .001). In conclusion, we observed a higher prevalence of vitamin D deficiency among obese participants and this was associated with a proatherogenic cardiometabolic risk profile.

Insulin, Thrombin, ERK1/2 Kinase and Vascular Smooth Muscle Cells Proliferation

Vascular smooth muscle cells (VSMC) respond to arterial wall injury by intimal proliferation and play a key role in atherogenesis by proliferating and migrating excessively in response to repeated injury, such as hypertension and atherosclerosis. In contrast, fully differentiated, quiescent VSMC allow arterial vasodilatation and vasoconstriction. Exaggerated and uncontrolled VSMC proliferation appears therefore to be a common feature of both atherosclerosis and hypertension. Signal transduction pathways in eukaryotic cells integrate diverse extracellular signals, and regulate complex biological responses such as growth, differentiation and death. One group of proline-directed Ser/Thr protein kinases, the mitogen-activated protein kinases (MAPKs), plays a central role in these signalling pathways. Much attention has focused in recent years on subfamilies of MAPKs, the extracellular signal regulated kinases (ERKs). Here we overview the work on ERKs 1 to 2, emphasising when possible their biological activities in VSMC proliferation. It is clear from numerous studies including our own, that ERK1/ERK2 pathway has an important role in VSMC proliferation induced by insulin (INS) and thrombin. Despite the physiological and pathophysiological importance of INS and thrombin, possible signal transduction pathways involved in INS and thrombin regulation of VSMCs proliferation remains poorly understood. Thus, this review examines recent findings in signaling mechanisms involved in INS and thrombin- triggered VSMCs proliferation with particular emphasis on ERK1/2 signaling pathways. Future investigations should now focus on the mechanisms of MAPK activation which might therefore represent a new mechanism involved in the antiproliferative effect revealed in this review.

Vitamin D and Dysfunctional Adipose Tissue in Obesity.

Vitamin D deficiency and dysfunctional adipose tissue are involved in the development of cardiometabolic disturbances (eg, hypertension, insulin resistance, type 2 diabetes mellitus, obesity, and dyslipidemia). We evaluated the relation between vitamin D and adipocytokines derived from adipose tissue. We studied 50 obese individuals who were classified into different subgroups according to medians of observed anthropometric parameters (body mass index, body fat percentage, waist circumference, and trunk fat mass). There was a negative correlation between vitamin D level and leptin and resistin (r = −.61, P < .01), while a positive association with adiponectin concentrations was found (r = .7, P < .001). Trend estimation showed that increase in vitamin D level is accompanied by intensive increase in adiponectin concentrations (growth coefficient: 12.13). In conclusion, a positive trend was established between vitamin D and the protective adipocytokine adiponectin. The clinical relevance of this relationship needs to be investigated in larger studies.

The relationship between vitamin D and obesity

Abstract Currently, vitamin D deficiency and obesity are pandemic diseases and they are associated with cardiovascular (CV) disease, metabolic syndrome and type 2 diabetes mellitus (T2DM) and other diseases. Concentrations of 25-hydroxyvitamin D (25(OH)D) (25D) are considered as the best indicator of total body vitamin D stores. An association between reduced circulating 25D concentrations and obesity is well known, but the mechanisms are not totally clear. The role of vitamin D supplementation is still uncertain and prospective interventions will establish its influence, if any, in the treatment of obesity. Vitamin D deficiency is associated with the presence of a cardiometabolic risk profile in the obese. Future trials may establish a role for Vitamin D supplementation in individuals at increased CV risk.

A review of the cardiovascular and anti-atherogenic effects of ghrelin.

Ghrelin is a peptide hormone produced mainly in the stomach that has widespread tissue distribution and diverse hormonal, metabolic and cardiovascular activities. The circulating ghrelin concentration increases during fasting and decreases after food intake. Ghrelin secretion may thus be initiated by food intake and is possibly controlled by nutritional factors. Lean subjects have increased levels of circulating ghrelin compared with obese subjects. Recent reports show that low plasma ghrelin is associated with elevated fasting insulin levels, insulin resistance and type 2 diabetes mellitus. Factors involved in the regulation of ghrelin secretion have not yet been defined; however, it is assumed that blood glucose levels represent a significant regulator. Recent evidence indicates that ghrelin can increase myocardial contractility, enhance vasodilatation, and has protective effect from myocardial damage. It has been shown that ghrelin may improve cardiac function through growth hormone (GH)-dependent mechanisms but there is also evidence to suggest that ghrelins cardioprotective activity is independent of GH. Recent data demonstrate that ghrelin can influence key events in atherogenesis. Thus, ghrelin may be a new target for the treatment of some cardiovascular diseases. In this review, we consider the current literature focusing on ghrelin as a potential antiatherogenic agent in the treatment of various pathophysiological conditions.

Nitric Oxide and its Role in Cardiovascular Diseases

Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide (NO) generation. NO is a free radical which reacts with various molecules to cause multiple biological effects. It is clear that the generation and actions of NO under physiological and pathophysiological conditions are exquisitely regulated and extend to almost every cell type and function within the circulation. While the molecule mediates many physiological functions, an excessive presence of NO is toxic to cells. The enzyme NOS, constitutively or inductively, catalyses the production of NO in several biological systems. NO is derived not only from NOS isoforms but also from NOS-independent sources. In mammals, to date, three distinct NOS isoforms have been identified: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The molecular structure, enzymology and pharmacology of these enzymes have been well defined, and reveal critical roles for the NOS system in a variety of important physiological processes. This review focuses on recent advances in the understanding of the interactions between NOS enzymes and pathophysiology of cardiovascular diseases (CVD) and the role of NO agonists as potential therapeutic agents in treatment of CVD.

Regulation of Endothelial Nitric Oxide Synthase in Pathophysiological Conditions

The nitric oxide (NO) cascade and endothelial NO synthase (eNOS) are best known for their role in endothelium-mediated relaxation of vascular smooth muscle (VSM). NO generated by eNOS has been established as a key regulatory signaling molecule in the vasculature. The activities of eNOS are controlled by intracellular calcium/calmodulin (CaM) and by binding of the molecular chaperone heat-shock protein 90 (Hsp90). A number of studies have demonstrated a close association between insulin resistance (IR) and NO bioactivity. Some recent studies demonstrate that insulin signaling is essential for normal cardiovascular (CV) function and lack of it such as IR result in CV dysfunction and disease. A key step in the initiation and progression of atherosclerosis is a reduction in the bioactivity of endothelial cell-derived NO. Multiple changes in endothelial function and eNOS activity accompany the onset and development of Type 2 diabetes mellitus (T2DM) and contribute to the development of cardiovascular disease (CVD). This review focuses on recent findings about regulation of eNOS in pathophysiological conditions such are: IR, T2DM and CVD.

Interrelatedness between C-reactive protein and oxidized low-density lipoprotein

Abstract C-reactive protein (CRP) is a marker of inflammation. Atherosclerosis is now recognized as inflammatory disease, and it seems that CRP directly contributes to atherogenesis. Oxidation of low-density lipoprotein (LDL) molecule increases the uptake of lipid products by macrophages leading to cholesterol accumulation and subsequent foam cell formation. The elevated levels of high sensitivity CRP (hsCRP) and oxidized LDL (OxLDL) in the blood were found to be associated with cardiovascular diseases (CVD). In this review, we highlighted the evidence that CRP and OxLDL are involved in interrelated (patho) physiological pathways. The findings on association between hsCRP and OxLDL in the clinical setting will be also summarized.