LVH is one of the most common target organ damages of hypertension It is the compensatory response of the heart to increased after-load, and also a risk factor of complications and prognosis deterioration. Currently, LVH is used as an independent risk factor for evaluation of cardiovascular diseases. LVH can lead to decreased blood flow reserve of coronary arteries and further myocardial ischemia. LVH also reduces left ventricular function, the cardiac contractile function of LVH patients is lower than that of normal people. Lack of energy supply of hypertrophic cardiomyocytes or metabolic disorders can aggravate the necrosis and fibrosis of cardiomyocytes. Then the whole cardiac contraction function and cardiac compliance would decrease, leading to the decompensation of cardiac function and heart failure . LVH could also lead to alterations of cardiac cells and interstitial structures, causing electrophysiological abnormalities. In addition, the imbalance between coronary blood supply and myocardial area resulted from LVH could lead to cardiac ischemia and changes in the regulation of cardiac autonomic nerve function, which also leads to abnormal myocardial electrical activity and eventually arrhythmia . Previous studies indicated that patients with hypertension showed that LVH reversal reduced overall cardiovascular event risk by 46%. Prevention and/or reversal of LVH can reduce the incidence and mortality of cardiovascular diseases and improve the prognosis of patients with hypertension [9, 10].
Hypertension is considered as a low inflammatory disease. Inflammatory response plays an important role in the occurrence and development of target organ damages in hypertension . Monocyte/macrophage system is the main effector cell of innate immunity. It can be divided into two categories according to the activation mode and immune function. Interferon-γ (IFN-γ) induces macrophage M1 polarization (proinflammatory), which is called " classical activation type ". Interleukin-4 (IL-4) induces macrophage M2 polarization (anti-inflammatory), which is classified as " alternative activation type " . The identification of macrophage subsets is based on the expression of specific extracellular and intracellular proteins. The markers of M1 macrophages include CD68, major histocompatibility complex-II (MHC-II), CD80, CD86, CC chemokine receptors, MCP-1, etc. on the cell surface. The markers of M2 macrophages include CD163, cx3c chemokine receptor 1 (CX3CR1), CD206, vascular endothelial growth factor (VEGF) and so on. TNF-α, IL-1β, IL-6, IL-12, IL-18, IL-23 and other proinflammatory factors were highly expressed in M1 type macrophages, while CD163, CD206, IL-10 and other anti-inflammatory factors were highly expressed in M2 type macrophages. Macrophages participate in the progression of hypertension and target organ damage. There are more pro-inflammatory monocytes in the circulation of hypertensive patients than those with normal blood pressure. Meanwhile, the levels of some pro-inflammatory cytokines increased in hypertensive patients [13–15]. Previous study found that the expression of CD163 and CD206 in SHR was decreased. After the activation of M2-type macrophages, the M1/M2 ratio was reduced, and the blood pressure of SHR gradually returned to normal . It was proved that the level of TNF-α was positively correlated with the degree of LVH in hypertensive patients[17, 18]. Inhibiting the nuclear factor-κB (NF-κB) pathway could lead to the increase of IL-10, which represent M2-type macrophage. IL-10 may inhibit angiotensin via NF-κB pathway, thereby inhibit fibroblast proliferation and collagen synthesis, and eventually inhibiting myocardial interstitial fibrosis, indicating that IL-10 may have the effect of preventing and reversing hypertension LVH [19, 20]. In this study, the expression of CD163 and CD206 in peripheral blood monocytes and the concentrations of IL-10 and TNF-α in serum of the hypertensive patients were detected, and also the healthy participants. It was found that the expression of CD163 and CD206 and the concentration of IL-10 in LVH group were lower than those in healthy and non-LVH groups, while the concentration of TNF-α was significantly higher compared to the other two groups. The results indicated that inflammation was activated in hypertensive patients with LVH. The expression of pro-inflammatory factors increased and the expression of anti-inflammatory factors decreased, and monocytes in the blood were mainly pro-inflammatory M1-type in hypertensive patients with LVH. It suggested that the occurrence and development of LVH were related to the alterations of monocytes/macrophages phenotype and inflammatory status.
Irbesartan is a commonly used antihypertensive drug. Recent studies have shown that oral administration of Irbesartan can reverse hypertension LVH and reduce LVMI in addition to control blood pressure [21, 22]. Possible mechanisms include Irbesartan inhibits renin-angiotensin-aldosterone system (RAAS), reduces the level of AngII and blocks the binding of AngII to AT1R, so as to improve the metabolism of myocardial fibroblasts and reduce myocardial hypertrophy. In addition, Irbesartan can improve autonomic nerve function, maintain the balance of sympathetic and parasympathetic nerves, and reduce target organ damage caused by nerve dysfunction. Previous experiment proved that ARB could block NF-κB signaling pathway, inhibit the release of inflammatory cytokines, so that to prevent or ameliorate target organ damages of hypertension . In this study, monocytes isolated from peripheral blood of hypertensive patients with LVH were stimulated by different concentrations of Irbesartan, the expression of CD163 and CD 206 in monocytes and the concentrations of IL-10 and TNF-α in the supernatant of the cells were determined. We found that Irbesartan could upregulate the expression of CD163 and CD206 in monocytes of hypertensive patients with LVH in a concentration-dependent manner, of which the group of 10− 6 mol/L was the most significant. Irbesartan could also increase the expression of IL-10 and inhibit the expression of TNF-α in monocytes culture supernatant of hypertensive patients with LVH in a concentration-dependent manner, of which the group of 10− 6 mol/L was the most significant. These results indicated that Irbesartan could change monocyte phenotype and inflammatory status in hypertensive patients with LVH. The possible mechanisms include the antioxidant effect of Irbesartan. The physicochemical stimulation of monocytes/macrophages by Irbesartan with different concentrations leads to autophagy of monocytes/macrophages, and then the functional status of monocytes/macrophages is changed. Finally, the inflammatory factors released from monocytes/macrophages were changed [24, 25]. The specific mechanism remains to be further explored. In this study, through the in vitro experiments, it was verified for the first time that Irbesartan could change the monocyte phenotype and inflammatory status of hypertensive patients with LVH. Meanwhile, Irbesartan could control blood pressure and reverse LVH by way of immune inflammation regulation, providing a new direction for hypertensive target organ damage protection. However, there were still several defects in this study, such as the sample size was relatively small, which would easily lead to statistical bias and experimental deviation. And further clinical studies were needed to confirmed the result of the in vitro studies.