Autoimmunity Against AT1 Receptor Spurs Endothelial Cellular Senescence and Vascular Aging

The presence of antibodies against the angiotensin II receptor (AT1 receptor) has been noted in a number of conditions involving raised blood pressure, from preeclampsia during pregnancy to the hypertension associated with aging. These antibodies induce dysfunction in vascular smooth muscle, preventing appropriate contraction and dilation in response to circumstances. That in and of itself is enough to produce hypertension, chronically raised blood pressure. In turn, that raised blood pressure causes damage to delicate tissues throughout the body, such as those of the kidney and the brain. It is an important aspect of aging, a way in which low-level molecular damage and disarray localized to blood vessels is converted to structural damage and progressive organ failure throughout the body.

In this context, the novel aspect of today's open access paper is the evidence for AT1 receptor antibodies to induce cellular senescence in vascular tissue, not that it also causes signs of vascular aging. From the research of recent years, it is clear that the accumulation of lingering senescent cells contributes to cardiovascular aging in a number of different ways, such as smooth muscle dysfunction, calcification of soft tissues, and foam cell behavior in atherosclerosis. There are a number of other conditions unrelated to aging in which excessive numbers of senescent cells play a role, such as type 1 diabetes. So it should perhaps not be unexpected at this point to find that additional conditions, such as preeclampsia, may be mediated in large part by cellular senescence.

The accumulation of senescent cells is, of course, a cause of aging. This point is now widely accepted in the research community, and senescent cells are the subject of growing research and development efforts largely focused on the production of senolytic therapies capable of safely and selectively destroying these errant cells in aged tissues. Senescent cells cause harm via a potent mix of secreted molecules that spur chronic inflammation, degrade surrounding tissue structure, and change the behavior of surrounding cells for the worse. Removing these cells quite quickly reverses specific measures of aging and age-related disease in animal models, and the first human trials are underway. Vascular aging is one of the likely areas of benefit - though if there is a mechanism such as autoimmunity spurring more rapid creation of senescent cells, then senolytic treatments will probably have to be correspondingly more frequent.

Autoantibodies against AT1 Receptor Contribute to Vascular Aging and Endothelial Cell Senescence

As a key regulator of vascular physiology, the renin-angiotensin system (RAS) has been implicated in the development and progression of vascular aging. Interruption of the RAS pathway, either by preventing the formation of angiotensin II (Ang II) or by blocking the Ang II type 1 (AT1) receptor, has been proven to be highly successful in retarding vascular aging phenotypes. Meanwhile, inappropriate activation of the RAS, independent of the classic bioactive molecule Ang II, may cause excessive activation of the AT1 receptor and induce chronic inflammation, but how this occurs is not fully understood.

At the end of the twentieth century, a specific autoantibody against AT1 receptor (AT1-AA) was discovered and found to exist in patients with preeclampsia, malignant hypertension, refractory hypertension, and renal-allograft rejection. AT1-AAs could specifically bind to the AT1 receptor and were found to have a receptor agonist-like effect. AT1-AAs were proven to be pro-inflammatory via the transcription factor nuclear factor-kappa B (NF-κB) pathway, thus enhancing the expression of inflammatory factors in endothelial cells (ECs). Moreover, we have previously demonstrated that AT1-AAs induced endothelial damage and contributed to endothelial dysfunction in vivo. Most importantly, AT1-AAs have been reported to accelerate aortic atherosclerosis in mice. A recent study demonstrated that higher AT1-AAs level was associated with inflammation, hypertension, and adverse outcomes. All the above evidence suggests a close relationship between AT1-AAs and vascular aging. Nevertheless, whether AT1-AAs can induce vascular aging or EC senescence has never been explored.

In this study, AT1-AAs were detected in the sera of patients with peripheral arterial disease (PAD) and the positive rate was 44.44% vs. 17.46% in non-PAD volunteers. In addition, analysis showed that AT1-AAs level was positively correlated with PAD. To reveal the causal relationship between AT1-AAs and vascular aging, an AT1-AAs-positive rat model was established by active immunization. The carotid pulse wave velocity was higher, and the aortic endothelium-dependent vasodilatation was attenuated significantly in the immunized rats. Morphological staining showed thickening of the aortic wall. Histological examination showed that levels of the senescent markers were increased in the aortic tissue, mostly located at the endothelium. In addition, purified AT1-AAs-IgGs from both the immunized rats and PAD patients induced premature senescence in cultured human umbilical vein endothelial cells. These effects were significantly blocked by the AT1 receptor blocker. Taken together, our study demonstrates that AT1-AAs contribute to the progression of vascular aging and induce EC senescence through AT1 receptor.

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