Role of inflammation, immunity, and oxidative stress in hypertension: New insights and potential therapeutic targets

Abstract

Hypertension is regarded as the most prominent risk factor for cardiovascular diseases, which have become a primary cause of death, and recent research has demonstrated that chronic inflammation is involved in the pathogenesis of hypertension. Both innate and adaptive immunity are now known to promote the elevation of blood pressure by triggering vascular inflammation and microvascular remodeling. For example, as an important part of innate immune system, classically activated macrophages (M1), neutrophils, and dendritic cells contribute to hypertension by secreting inflammatory cy3tokines. In particular, interferon-gamma (IFN-γ) and interleukin-17 (IL-17) produced by activated T lymphocytes contribute to hypertension by inducing oxidative stress injury and endothelial dysfunction. However, the regulatory T cells and alternatively activated macrophages (M2) may have a protective role in hypertension. Although inflammation is related to hypertension, the exact mechanisms are complex and unclear. The present review aims to reveal the roles of inflammation, immunity, and oxidative stress in the initiation and evolution of hypertension. We envisage that the review will strengthen public understanding of the pathophysiological mechanisms of hypertension and may provide new insights and potential therapeutic strategies for hypertension.

Keywords: cardiovascular diseases; cytokines; hypertension; immunity; inflammation; oxidative stress.

Figure 1

Classic mechanisms of inflammasome activation. Lipopolysaccharide (LPS), which is regarded as the prototype of pathogen associated molecular patterns (PAMPs) and heat shock proteins (HSPs) as a typical representative of damage associated molecular patterns (DAMPs), can be recognized by toll-like receptor 4 (TLR4). Nuclear factor kappa B (NFκB) mediates these signals to produce NOD-like receptor family pyrin domain containing 3 (NLRP3), pro-IL-1β, pro-IL-18, and pro-IL-37. Next, NLRP3 is activated by potassium (K+) efflux, calcium (Ca2+) influx, and lysosomal leakage to recruit cysteine-requiring aspartate protease-1 (caspase-1). Caspase-1 then induces the maturation and release of pro-IL-1β, pro-IL-18, and pro-IL-37 and other related inflammatory agents that cause the inflammatory reaction and participate in the occurrence and development of the disease.

Figure 2

Role of inflammation and immunity in hypertension. Many risk factors, such as genetic susceptibility, high salt, and environmental stress, can elevate blood pressure (BP) and consequently activate the sympathetic nerve system (SNS) or inhibit the parasympathetic nerve system (PNS). Over time, elevated BP can induce organ injury promoting the formation of damage-associated molecular patterns (DAMPs) and new antigens. In addition, several infectious diseases can enhance the activation of the innate immune system through the binding of pathogen-associated molecular patterns (PAMPs) to toll-like receptors. DAMPs, new antigens, and PAMPs activate innate immunity which interacts with adaptive immunity. Next, numerous proinflammatory cytokines are released and result in further organ injury. Through alternatively activated macrophages (M2) and Tregs have roles in anti-inflammatory response, the effect is too weak to reduce the organ damage. Finally, peripheral vascular resistance and blood volume increases to result in hypertension (Created with BioRender.com).

Figure 3

Mechanisms of oxidative stress causing hypertension in vascular endothelial cells. Ang II and ET-1 can stimulate NADPH oxidase and mitochondria to produce ROS (e.g., H2O2 and OFR), which are recognized by their receptors on the endothelial cells. ROS stimulate the PI3K/Akt-MAPK pathway to inhibit the expression of eNOS mRNA and eNOS activity, thus reducing the availability of NO, which results in vasodilation insufficiency and elevation of blood pressure. Moreover, angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs) and vitamin C (VC) may be potential therapeutic strategies in the process of oxidative stress.