Alexander N. Orekhov

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.

Macrophages and Their Contribution to the Development of Atherosclerosis

Atherosclerosis can be regarded as chronic inflammatory disease driven by lipid accumulation in the arterial wall. Macrophages play a key role in the development of local inflammatory response and atherosclerotic lesion growth. Atherosclerotic plaque is a complex microenvironment, in which different subsets of macrophages coexist executing distinct, although in some cases overlapping functions. According to the classical simplified nomenclature, lesion macrophages can belong to pro-inflammatory or anti-inflammatory or alternatively activated types. While the former promote the inflammatory response and participate in lipid accumulation, the latter are responsible for the inflammation resolution and plaque stabilisation. Atherosclerotic lesion dynamics depends therefore on the balance between these macrophages populations. The diverse functions of macrophages make them an attractive therapeutic target for the development of novel anti-atherosclerotic treatments. In this chapter, we discuss different types of macrophages and their roles in atherosclerotic lesion dynamics and describe the results of several experiments studying macrophage polarisation in atherosclerosis.

Potential use of buccal epithelium for genetic diagnosis of atherosclerosis using mtDNA mutations

1Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, Moscow 121552, Russia. 2Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow 125315, Russia. 3Department of Genetics, Southern Federal University, Rostov-on-Don 344006, Russia. 4Institute for Atherosclerosis Research, Skolkovo Innovative Centre, Moscow 121609, Russia. 5Federal Scientific Clinical Center for Resuscitation and Rehabilitation, Moscow 109240, Russia.

New markers of atherosclerosis: a threshold level of heteroplasmy in mtDNA mutations

1Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, 121552 Moscow, Russia. 2Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia. 3Institute for Atherosclerosis Research, Skolkovo Innovative Centre, 121609 Moscow, Russia. 4Unit for the Study of Morphology and Arterial Function, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy.

Chemical composition of circulating native and desialylated low density lipoprotein: what is the difference?

1Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia. 2INSERM UMR_S 1166, Faculty of Medicine Pitie-Salpetriere, Bld de L’Hopital 91, University of Pierre and Marie Curie-Paris 6, 75013 Paris, France. 3Federal Scientific Clinical Center for Resuscitation and Rehabilitation, 109240 Moscow, Russia. 4Institute for Atherosclerosis Research, Skolkovo Innovative Center, 121609 Moscow, Russia.

Small dense and desialylated low density lipoprotein in diabetic patients

1Department of Cardiovascular Pathology, Russian Cardiology Research and Production Complex, 121552 Moscow, Russia. 2Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia. 3Department of Genetics, Southern Federal University, 344090 Rostov-on-Don, Russia. 4Institute for Atherosclerosis Research, Skolkovo Innovative Center, 121609 Moscow, Russia. 5Federal Scientific Clinical Center for Resuscitation and Rehabilitation, 109240 Moscow, Russia.

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 character‐ ized 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 re‐ duction in the lipid core mass, which would followed by plaque stabilization. Taken togeth‐ er, these approaches could theoretically result in the regression of arterial lesions.

Is insulin pro-atherogenic at the cellular level?

1Department of Cardiovascular Pathology, National Medical Research Center of Cardiology, 121552 Moscow, Russia. 2Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia. 3Federal Scientific Clinical Center for Resuscitation and Rehabilitation, 109240 Moscow, Russia. 4Institute for Atherosclerosis Research, Skolkovo Innovative Center, 121609 Moscow, Russia.

Circulating Atherogenic Multiple-Modified Low-Density Lipoprotein: Pathophysiology and Clinical Applications

Low-density lipoprotein (LDL) circulating in human bloodstream is the source of lipids that accumulate in arterial intimal cells in atherosclerosis. In-vitro–modified LDL (acetylated, exposed to malondialdehyde, oxidized with transition metal ions, etc.) is atherogenic, that is, it causes accumulation of lipids in cultured cells. We have found that LDL circulating in the atherosclerosis patients’ blood is atherogenic, while LDL from healthy donors is not. Atherogenic LDL was found to be desialylated. Moreover, only the desialylated subfraction of human LDL was atherogenic. Desialylated LDL is generally denser, smaller, and more electronegative than native LDL. Consequently, these LDL types are multiply modified, and according to our observations, desialylation is probably the principal and foremost cause of lipoprotein atherogenicity. It was found that desialylated LDL of coronary atherosclerosis patients was also oxidized. Complex formation further increases LDL atherogenicity, with LDL associates, immune complexes with antibodies recognizing modified LDL and complexes with extracellular matrix components being most atherogenic. We hypothesized that a nonlipid factor might be extracted from the blood serum using a column with immobilized LDL. This treatment not only allowed revealing the nonlipid factor of blood atherogenicity but also opened the prospect for reducing atherogenicity in patients.

Cell Composition of the Subendothelial Aortic Intima and the Role of Alpha-Smooth Muscle Actin Expressing Pericyte-Like Cells and Smooth Muscle Cells in the Development of Atherosclerosis

The cell composition of the human arterial intima has been intensely studied but is still not well understood. The majority of cell population in normal and atherosclerotic intima is represented by cells expressing smooth muscle α-actin, which are thought to be smooth muscle cells. Some antigens, which are absent in medial smooth muscle cells, were detected in intimal smooth muscle cells. In particular, using 3G5 antiper‐ icyte antibody, presence of stellate-shaped pericyte-like resident cells in normal and atherosclerotic human aortic intima has been found. In all analyzed aortic tissue specimens, 3G5+ cells were found to account for more than 30% of the total intimal cell population of undiseased intima. In the atherosclerotic lesions, the number of 3G5+ cells becomes notably lower than that in undiseased intima. The use of 2A7 antibody that identifies activated pericytes revealed the presence of 2A7+ cells in atherosclerotic plaques, while no 2A7+ cells were detected in normal intima. The strongest correlation was established between the number of pericyte-like cells and the content of intimal lipids. The correlation coefficients between the number of pericyte-like cells and collagen content and intimal thickness were greater than the correlation coefficients for smooth muscle cells. On the basis of these findings, pericyte-like cells but not smooth muscle cells or other cell types have been declared to be the key cellular element driving the formation of atherosclerotic lesions. The present chapter aims to detail the abovementioned issues. The present chapter also aims to promote a view that α-smooth muscle actin+ pericyte-like cells represent the key players in the development of atherosclerotic lesions.