A current view of G protein-coupled receptor - mediated signaling in pulmonary hypertension: finding opportunities for therapeutic intervention

Strassheim, Derek; Karoor, Vijaya; Stenmark, Kurt R.; Verin, Alexander D.; Gerasimovskaya, Evgenia

doi:10.20517/2574-1209.2018.44

Cited by 22 publications

(14 citation statements)

References 252 publications

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“…These two processes do interact [45], but it remains uncertain regarding the true primary driver in this interaction. Indeed, changes in cholesterol metabolism can affect inflammatory responses of macrophages [37][38][39][40]43,[46][47][48]. However, we recently revealed ten genes that may be the key regulators of foam cell formation [25].…”

Section: Discussionmentioning

confidence: 99%

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our Int.Int. J. Mol. Sci. 2020, 21, 2716 2 of 17 group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is 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. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

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Section: Discussionmentioning

confidence: 99%

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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“…Many studies have suggested that the development of certain autoimmune diseases was associated with a decrease in the overall level of IgG sialylation. In the cases of individual nosologies, a relationship has been found between total IgG or IgG autoantibodies decreased sialylation and the pathological activity of autoantibodies [37], and with severity of disease symptoms [38], its activity and course [39,40], and the response to treatment [41,42].…”

Section: Glycosylation Of Immunoglobulins: the Effects In Various Dismentioning

confidence: 99%

Sialylated Immunoglobulins for the Treatment of Immuno-Inflammatory Diseases

Markina

Gerasimova

Markin

et al. 2020

IJMS

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Immunoglobulins are the potent effector proteins of the humoral immune response. In the course of evolution, immunoglobulins have formed extremely diverse types of molecular structures with antigen-recognizing, antigen-binding, and effector functions embedded in a single molecule. Polysaccharide moiety of immunoglobulins plays the essential role in immunoglobulin functioning. There is growing evidence that the carbohydrate composition of immunoglobulin-linked glycans, and especially their terminal sialic acid residues, provide a key effect on the effector functions of immunoglobulins. Possibly, sialylation of Fc glycan is a common mechanism of IgG anti-inflammatory action in vivo. Thus, the post-translational modification (glycosylation) of immunoglobulins opens up significant possibilities in the diagnosis of both immunological and inflammatory disorders and in their therapies. This review is focused on the analysis of glycosylation of immunoglobulins, which can be a promising addition to improve existing strategies for the diagnosis and treatment of various immuno-inflammatory diseases.

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“…Thanks to these results, inflammation regained the attention as possible point of therapeutic intervention for atherosclerosis treatment. However, it appeared to be more promising to target specific proinflammatory pathways rather than inflammation in general [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

Poznyak

Melnichenko

et al. 2020

Cells

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Atherosclerosis is associated with acute cardiovascular conditions, such as ischemic heart disease, myocardial infarction, and stroke, and is the leading cause of morbidity and mortality worldwide. Our understanding of atherosclerosis and the processes triggering its initiation is constantly improving, and, during the last few decades, many pathological processes related to this disease have been investigated in detail. For example, atherosclerosis has been considered to be a chronic inflammation triggered by the injury of the arterial wall. However, recent works showed that atherogenesis is a more complex process involving not only the immune system, but also resident cells of the vessel wall, genetic factors, altered hemodynamics, and changes in lipid metabolism. In this review, we focus on foam cells that are crucial for atherosclerosis lesion formation. It has been demonstrated that the formation of foam cells is induced by modified low-density lipoprotein (LDL). The beneficial effects of the majority of therapeutic strategies with generalized action, such as the use of anti-inflammatory drugs or antioxidants, were not confirmed by clinical studies. However, the experimental therapies targeting certain stages of atherosclerosis, among which are lipid accumulation, were shown to be more effective. This emphasizes the relevance of future detailed investigation of atherogenesis and the importance of new therapies development.

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A current view of G protein-coupled receptor - mediated signaling in pulmonary hypertension: finding opportunities for therapeutic intervention

Cited by 22 publications

References 252 publications

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Sialylated Immunoglobulins for the Treatment of Immuno-Inflammatory Diseases

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

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