Use of Natural Products for Direct Anti-Atherosclerotic Therapy

Atherosclerosis and vascular disorders, which result from atherosclerosis, represent one of the major problems in the modern medicine and public health. Atherosclerosis is characterized by structural and functional changes of large arteries. The approaches for the treatment of atherosclerosis require at least the prevention of growth of atherosclerotic lesions and reduction in the lipid core mass, which would followed by plaque stabilization. Taken together, these approaches could theoretically result in the regression of arterial lesions. Atherosclerosis develops in the arterial wall and remains asymptomatic until ischemia of distal organs is evident. Therapy of clinical manifestations of atherosclerosis is largely aimed at reducing symptoms or affecting hemodynamic response and often does not affect the cause or course of disease, namely the atherosclerotic lesion itself. Of course, anti-atherosclerotic effects of statins revealed in many prospective clinical trials may be considered; however, statins have never been recognized as the drugs indicated just for direct treatment or prevention of atherosclerosis. They are used predominately in the course of hypolipidemic therapy, and the effects of treatment are estimated by success in reaching the target level of low density lipoprotein (LDL) cholesterol, but not the regression of atherosclerotic lesion or intimamedia thickness. The last should be considered as beneficial effect, which is mainly due to pleiotropic mechanisms of action. Atherosclerosis develops over many years, so anti-atherosclerotic therapy should be a long-term or even lifelong therapy. Tachyphylaxis, long-term toxicity and cost amongst other issues may present problems for the use of conventional medications in a long-term. Drugs based on natural products can be a good alternative

The Interaction of Plasma Sialylated and Desialylated Lipoproteins with Collagen from the Intima and Media of Uninvolved and Atherosclerotic Human Aorta

We have evaluated the binding of sialylated and desialylated lipoproteins to collagen isolated from the proteoglycan and musculoelastic layers of intima and media of uninvolved human aorta and atherosclerotic lesions. Comparing various collagen preparations from the uninvolved intima-media, the binding of sialylated apoB-containing lipoproteins was best to collagen from the intimal PG-rich layer. Binding of sialylated apoB-containing lipoproteins to collagen from this layer of fatty streak and fibroatheroma was 1.4- and 3.1-fold lower, respectively, in comparison with normal intima. Desialylated VLDL versus sialylated one exhibited a greater binding (1.4- to 3.0-fold) to all the collagen preparations examined. Desialylated IDL and LDL showed a higher binding than sialylated ones when collagen from the intimal layers of fibroatheroma was used. Binding of desialylated HDL to collagen from the intimal PG-rich layer of normal tissue, initial lesion, and fatty streak was 1.2- to 2.0-fold higher compared with sialylated HDL

The effects of time-released garlic powder tablets on multifunctional cardiovascular risk in patients with coronary artery disease

The double-blinded placebo-controlled randomized study has been performed in 51 coronary heart disease (CHD) patients to estimate the effects of time-released garlic powder tablets Allicor on the values of 10-year prognostic risk of acute myocardial infarction (fatal and non-fatal) and sudden death, with the respect of secondary CHD prevention. It has been demonstrated that 12-month treatment with Allicor results in the significant decrease of cardiovascular risk by 1.5-fold in men (p < 0.05), and by 1.3-fold in women. The above results were equitable also in terms of relative risks. The main effect that played a role in cardiovascular risk reduction was the decrease in LDL cholesterol by 32.9 mg/dl in men (p < 0.05), and by 27.3 mg/dl in women. Thus, the most significant effects were observed in men, while in women the decrease of cardiovascular risk appeared as a trend that might be due presumably to the insufficient sample size. Since Allicor is the remedy of natural origin, it is safe with the respect to adverse effects and allows even perpetual administration that may be crucial for the secondary prevention of atherosclerotic diseases in CHD patients

Lipid Regulators during Atherogenesis : expression of LXR, PPAR, and SREBP mRNA in the Human Aorta

Transcription factors LXRs, PPARs, and SREBPs have been implicated in a multitude of physiological and pathological processes including atherogenesis. However, little is known about the regulation of these transcription factors at different stages of atherosclerosis progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to compare the contents of mRNAs in pairs intact-injured aorta fragments taken from the same donors. Only minor changes in LXR?, LXR?, PPAR?, PPAR?, SREBP1, and SREBP2 mRNA levels were found in initial lesions as compared with intact non-diseased tissue. The contents of all mRNAs but SREBP2 mRNA were found to be progressively up-regulated in fatty streaks and fibrous lipoid plaques. These changes were only partially reproduced in cultured macrophages upon lipid loading. Wave-shaped changes in abundance of correlations between given group of mRNAs and 28 atherosclerosis-related mRNA species in the course of atherogenesis were observed. The impact of specific mRNA correlations on the total correlations also significantly varied between different lesion types. The study suggests that the extent and forms of LXR/PPAR/SREBP participation in intima functions vary nonlinear in individual fashion in atherogenesis. We speculate that the observed changes in mRNAs expression and coupling reflect shifts in lipid ligands availability and cellular composition in the course of atherosclerosis progression

Development of Antiatherosclerotic Drugs on the basis of Natural Products Using Cell Model Approach

Atherosclerosis including its subclinical form is one of the key medical and social problems. At present, there is no therapy available for widespread use against subclinical atherosclerosis. The use of synthetic drugs for the prevention of arteriosclerosis in its early stages is not sufficient because of the limited indications for severe side effects and high cost of treatment. Obviously, effective antiatherosclerotic drugs based on natural products would be a preferred alternative. Simple cell-based models for testing different natural products have been developed and the ability of natural products to prevent intracellular lipid accumulation in primary cell culture was evaluated. This approach utilizing cell models allowed to test effects of such direct antiatherosclerotic therapy, analyzing the effects mimicking those which can occur “at the level” of arterial wall via the inhibition of intracellular lipid deposition. The data from the carried out clinical trials support a point of view that the identification of antiatherosclerotic activity of natural products might offer a great opportunity for the prevention and treatment of atherosclerotic disease, reducing cardiovascular morbidity and mortality

Role of Endoplasmic Reticulum Stress in Atherosclerosis and Diabetic Macrovascular Complications

Age-related changes in endoplasmic reticulum (ER) are associated with stress of this cell organelle. Unfolded protein response (UPR) is a normal physiological reaction of a cell in order to prevent accumulation of unfolded and misfolded proteins in the ER and improve the normal ER function. However, in pathologic conditions such as atherosclerosis, obesity, and diabetes, ER function becomes impaired, leading to the development of ER stress. In chronic ER stress, defective posttranslational protein folding results in deposits of aberrantly folded proteins in the ER and the induction of cell apoptosis mediated by UPR sensors C/EBPα-homologous protein (CHOP) and inositol requiring protein-1 (IRE1). Since ER stress and ER-induced cell death play a nonredundant role in the pathogenesis of atherosclerosis and diabetic macrovascular complications, pharmaceutical targeting of ER stress components and pathways may be beneficial in the treatment and prevention of cardiovascular pathology

Pathophysiological Aspects of the Development of Abdominal Aortic Aneurysm with a Special Focus on Mitochondrial Dysfunction and Genetic Associations

Abdominal aortic aneurysm (AAA) is a complex degenerative vascular disease, with considerable morbidity and mortality rates among the elderly population. The mortality of AAA is related to aneurysm expansion (the enlargement of the aortic diameter up to 30 mm and above) and the subsequent rupture. The pathogenesis of AAA involves several biological processes, including aortic mural inflammation, oxidative stress, vascular smooth muscle cell apoptosis, elastin depletion, and degradation of the extracellular matrix. Mitochondrial dysfunction was also found to be associated with AAA formation. The evidence accumulated to date supports a close relationship between environmental and genetic factors in AAA initiation and progression. However, a comprehensive pathophysiological understanding of AAA formation remains incomplete. The open surgical repair of AAA is the only therapeutic option currently available, while a specific pharmacotherapy is still awaited. Therefore, there is a great need to clarify pathophysiological cellular and molecular mechanisms underlying AAA formation that would help to develop effective pharmacological therapies. In this review, pathophysiological aspects of AAA development with a special focus on mitochondrial dysfunction and genetic associations were discussed.This work was supported by the Russian Science Foundation (Grant # 20-45-08002).Scopu

Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response

Association of Mitochondrial Genetic Variation with Carotid Atherosclerosis

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