Abstract
Activation of Toll-like receptors (TLR) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of cardiovascular diseases. Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study we hypothesize that inhibition of TLR4 decreases blood pressure and improves vascular contractility in resistance arteries from spontaneously hypertensive rats (SHR). TLR4 protein expression in mesenteric resistance arteries was higher in 15 weeks-old SHR than in same age Wistar controls or in 5 weeks-old SHR. In order to decrease activation of TLR4, 15 weeks-old SHR and Wistar rats were treated with anti-TLR4 antibody or non-specific IgG control antibody for 15 days (1µg per day, i.p.). Treatment with anti-TLR4 decreased mean arterial pressure as well as TLR4 protein expression in mesenteric resistance arteries and interleukin-6 (IL-6) serum levels from SHR when compared to SHR treated with IgG. No changes in these parameters were found in Wistar treated rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to noradrenaline compared to IgG-treated-SHR. Inhibition of cyclooxygenase-1 (Cox) and Cox-2, enzymes related to inflammatory pathways, decreased noradrenaline responses only in mesenteric resistance arteries of SHR treated with IgG. Cox-2 expression and thromboxane A2 release were decreased in SHR treated with anti-TLR4 compared with IgG-treated-SHR. Our results suggest that TLR4 activation contributes to increased blood pressure, low grade inflammation and plays a role in the augmented vascular contractility displayed by SHR.
Highlights
Toll like receptor 4 (TLR4) is expressed on virtually all human cells and binds a wide spectrum of exogenous and endogenous ligands
The major findings of this study are that the treatment of adult spontaneously hypertensive rats (SHR) with anti-TLR4 antibody reduces mean arterial pressure as well as decreases contractile responses in mesenteric resistance arteries when compared to non-specific IgG-treated-SHR
In view of the decreased blood pressure observed after anti-TLR4 treatment in SHR, we investigated whether this treatment could improve contractile responses in resistance arteries from SHR
Summary
Toll like receptor 4 (TLR4) is expressed on virtually all human cells and binds a wide spectrum of exogenous (including bacterial lipopolysaccharide - LPS) and endogenous (heat shock protein, angiotensin II) ligands. TLR4 has been implicated in mediating chronic inflammatory diseases, including cardiovascular diseases.[3] TLR4 upregulation has been observed after myocardial infarction in the heart of mice[4] and it is related to the initiation and progression of atherosclerosis.[5] TLR4 expression is augmented in cardiomyocytes from spontaneously hypertensive rats (SHR), when compared with Wistar Kyoto rats, suggesting that this receptor may be implicated in the hypertension-associated end-organ damage.[6]
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