Arterial Hypertension and Interleukins: Potential Therapeutic Target or Future Diagnostic Marker?

Abstract

Hypertension as a multifactorial pathology is one of the most important cardiovascular risk factors, affecting up to 30-40% of the general population. Complex immune responses are involved in the inflammatory mechanism of hypertension, with evidence pointing to increased inflammatory mediators even in prehypertensive patients. Increased vascular permeability, thrombogenesis, and fibrosis, effects that are associated with sustained hypertension, could be attributed to chronic inflammation. Chronic inflammation triggers endothelial dysfunction via increased production of ROS through proinflammatory cytokines. Increased serum level of proinflammatory cytokines such as IL-1β, IL-6, IL-8, IL-17, IL-23, TGFβ, and TNFα in hypertensive patients has been associated with either increased blood pressure values and/or end-organ damage. Moreover, some cytokines (i.e., IL-6) seem to determine a hypertensive response to angiotensin II, regardless of blood pressure values. Understanding hypertension as an inflammatory-based pathology gives way to new therapeutic targets. As such, conventional cardiovascular drugs (statins, calcium channels blockers, and ACEIs/ARBs) have shown additional anti-inflammatory effects that could be linked to their blood pressure lowering properties. Moreover, anti-inflammatory drugs (mycophenolate mofetil) have been shown to decrease blood pressure in hypertensive patients or prevent its development in normotensive individuals. Further research is needed to evaluate whether drugs targeting hypertensive-linked proinflammatory cytokines, such as monoclonal antibodies, could become a new therapeutic option in treating arterial hypertension.

Figure 1

Etiology of the inflammatory process. Low level chronic inflammation increases the concentrations of markers and of inflammatory cells, leading to increased production of C-reactive protein (CRP) by the liver, in response to interleukin-6 (IL-6), which provokes a reduction in vasodilation and an increase in vascular damage. TNF-a: tumor necrosis factor alpha; IL-6: interleukin-6; CRP: C-reactive protein; NO: nitric oxide; ET-1: endothelin-1.

Figure 2

The inflammatory-mediated HTN process, immune cells via different signaling pathways. The known routes, like signal transducer and activator of transcription -1, -3, and -5 (STAT), janus-associated kinases (JAK), domain containing phosphatase (SHP2) or extracellular signal related kinase and phosphatidylinositol-3-kinase (PIK3/AKT), depend on the specific interleukin production.