Toll-Like Receptors, Hypertension, and an Antimalarial Drug

Abstract

The role of the immune system in the pathogenesis of hypertension is a growing area of research. Although the immune system had long been suspected to contribute to hypertension, only in the last decade have studies begun to define the roles of the participating immune cells and molecules involved in hypertension. [1][2][3][4] Toll-like receptors (TLRs) 5,6 are part of the innate immune system that recognize molecular patterns on various pathogens (pathogen-associated molecular patterns) and so called endogenous damage signals (damage-associated molecular patterns). These patterns may be proteins, lipids, carbohydrates, or nucleic acids. TLRs are expressed either on the cell surface or in intracellular endolysosomal compartment. Although the endogenous ligands of the TLRs that trigger hypertension have not been identified, disruption of TLR signaling has been shown to attenuate hypertension.In a study published last year in "Cardiovascular Research, " McCarthy et al. reported that intraperitoneal injection of a TLR9 inhibitory oligonucleotide ODN2088 in adult spontaneously hypertensive rats (SHR) decreased the systolic blood pressure, whereas injections of TLR9 agonist ODN2395 in normotensive rats increased the systolic blood pressure. 7 In their study published in the current issue of American Journal of Hypertension, 8 these investigators extend their findings by testing a mechanism of intracellular TLR activation, particularly TLR9, in SHR hypertension. Chloroquine, a drug known as an effective antimalarial therapeutic agent, blocks endosomal maturation 9 by inhibiting vesicular acidification that is also required for TLR9 signaling. 10 McCarthy et al. injected chloroquine in SHR to disrupt TLR9 signaling and measured expression of key molecular components of TLR signaling in mesenteric resistance vessels that significantly contribute to hypertension. The major finding of the study is that in young prehypertensive SHR (5 weeks old), disruption of intracellular TLR signaling by chloroquine decreased blood pressure. These findings are consistent with the authors' previous report as well as with the findings by Harwani et al. 11 demonstrating that the isolated splenocytes from prehypertensive SHR have an enhanced proinflammatory response to TLR 7/8 and 9 agonists in the presence of nicotine. In normotensive WistarKyoto rats, nicotine was anti-inflammatory. Moreover, in vivo infusion of nicotine in young prehypertensive SHR induces premature hypertension. 12 An important concept which evolves from this work is that the innate immune system is important in SHR hypertension. This concept is also shown to work in angiotensin II (Ang II) induced hypertension where priming of dendritic cells, a member of the innate immune system, by Ang II contributes to hypertension. 13 A second concept in this paper is the possible role of TLR adaptor protein MyD88. All TLRs, except intracellular TLR3, require MyD88 for signaling. Loss of MyD88 protein severely impairs TLR signaling and inflammatory responses. 14 In the study by Mc...

<p>Toll-like Receptors as a Potential Drug Target for Diabetes Mellitus and Diabetes-associated Complications</p>

“… 61 TLR1 or TLR6 LDLr–/– mice model (TLR2 has linkage with TLRs 1 and 6 in signal transmission, the model is used to identify the co-receptor of TLR2 involved in TLR2 mediated atherosclerosis) Although, depleting (TLRs 1 and 6) showed no effect on development of lesion without exogenous agonists, deficiency of TLRs 1 and 6 reduce the progression of atherosclerosis with exogenous TLR1 and TLR6 ligands, respectively (probably due to response of TLRs 1 and 6 for unidentified endogenous TLR2 ligands). 81 In Apo lipoprotein E–/– mice model Reduced TLR2 showed protection in the formation of aortic atherosclerotic plaque, might be because of reduced lipid aggregation and macrophage entry to aortic sinus in addition to decreed monocyte chemoattractant protein-1 (MCP-1) levels 82 Hypercholesterolemia rabbit model In the aorta, it was observed that mRNA expression of TLR3 was highly upregulated 83 In mice (wild type) and intact TLR3 Function of ECs was impaired due to systemic administration of TLR3 agonists 84 In mice model with LDLr–/– TLR 3 deficit in hematopoietic cells produces protection from the generation of atherosclerosis while the level of circulating lipids are unchanged 85 In Apo lipoprotein E–/– mice model TLR3 showed protection against arterial injury and atherogenesis while depletion of the receptor enhances formation of atherosclerosis 86 In mice with TLR3 deficiency It was observed that the amount of collagen and SMS was raised in the lesion of atherosclerosis implying the contribution of TLR3 to cause disturbance in the area of plaque due to partial controlling of the function of MMP-2 and MMP-9 in macrophages. 87 In human platelet It was showed that TLR3 in human platelet can promotes the aggregation of platelet, release of ATP release, and stimulation of integrin.…”