Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats

Abstract

Inappropriate immune system activation has been proposed as a unifying mechanism linking the 3 major organ systems that are dysregulated in the development and maintenance of hypertension-the cardiovascular system, the kidneys, and the autonomic nervous system. 1,2 However, the exact mechanisms that initiate this deleterious response, thereby contributing to further increases in blood pressure, are not well understood. 1,2 Although the participation of the adaptive immune system, and specifically T cells, in the pathogenesis of hypertension is not in question, 3,4 there are still gaps surrounding how it is signaled for involvement in the first place.Immune system recognition and response to danger is becoming apparent in a wide range of disease states, including cardiovascular diseases. 5 In this paradigm, the immune system responds to stimuli that it perceives as indicative of danger. 6 As such, molecules released from cell injury and death, called damage-associated molecular patterns (DAMPs), as well as pathogen-associated molecular patterns, signals to the immune system that a response is required. Normally, endogenous molecules are shielded from the immune system via compartmentalization within plasma membranes. However, when a cell dies or undergoes undue stress, these molecules can be released and are able to activate pattern recognition receptors on immune and nonimmune cells. 5 Toll-like receptors (TLR) are a class of innate immune system pattern recognition receptors that recognize and respond to DAMPs. 2,7 We have recently observed that mitochondrial DNA (mtDNA), a DAMP that activates TLR9, is increased in the circulation of spontaneously hypertensive rats (SHR). 8 Specifically, TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) dinucleotides and these are common in prokaryotic DNA and mtDNA, but not nuclear DNA. 9 Upon recognition of unmethylated CpG dinucleotides in BACKGROUNDInnate immune system responses to damage-associated molecular patterns (DAMPs) are involved in hypertension. However, the mechanisms of this contribution are not well understood. Circulating mitochondrial DNA is a DAMP that activates Toll-like receptor (TLR) 9 and is elevated in spontaneously hypertensive rats (SHR). Therefore, we hypothesized that lysosomotropic agent chloroquine (CQ) would impair TLR9 signaling, as well as prevent the development of hypertension and immune cell recruitment to the vasculature, in SHR.

Autophagy inhibition by chloroquine prevents increase in blood pressure and preserves endothelial functions

“…In this context, the results of the present work demonstrated that the enhanced endothelial cell autophagy could be of pathological significance during hypertension. In the present study, prolonged treatment with CHQ prevented the increase in the blood pressure in the renovascular hypertensive rats, which corroborated with a recent study that reported inhibition of hypertension with the use of CHQ in spontaneously hypertensive rats [20]. Confirming the findings of the in vitro investigations conducted in the present study, CHQ also inhibited the upregulation in the vascular autophagy flux in the aorta of the renovascular hypertensive rats, which represent a RAASdependent model of hypertension.…”

Repurposing New Use for Old Drug Chloroquine against Metabolic Syndrome: A Review on Animal and Human Evidence

“…Therapeutic CQ at the dose of 40 mg/kg/day (i.p.) for 21 days significantly reduced systolic blood pressure (SBP) in spontaneous hypertensive rats of two different ages 66 , 67 . In humans, McGill et al designed a trial to administer CQ dose escalations (80 mg/week for three weeks followed by 80 mg/day for three weeks and 250 mg/day for three weeks) in MetS patients.…”

“…These observations were found in young but not in adult spontaneous hypertensive rats. The authors suggested that the downstream TLR-signalling proteins might be more sensitive to CQ treatment in the young animals, therefore a higher dose of CQ might be needed to exert immunomodulatory effects in the adult animals 66 .…”

Paying the Toll for Inflammation

“…These data led to the hypothesis that TLR9 contributes to the etiology of hypertension 11 . Consequently, we subsequently inhibited TLR9 in spontaneously hypertensive rats (SHR) in vivo with the use of the ODN2088 (specific antagonist) 42 and chloroquine (non-specific inhibitor) 8,47 . Consistent with our initial observations, we observed that TLR9 inhibition in SHR was able to improve endothelial function of resistance and conduit arteries, and lower blood pressure.…”