AT1R antagonist (Alchemedicine)

Background/Objectives: Copper is an essential micronutrient required for physiological functions, but elevated serum levels impair vascular reactivity and blood pressure regulation. Given PVAT's critical role in vascular function, this study aimed to investigate the effects of chronic copper overload on the secretory function of mesenteric PVAT, focusing on its vasoregulatory role. Methods: In the first phase, 8-week-old male Wistar rats were assigned to two groups, namely control (saline, i.p.) or copper (25.72 µg/kg/day Cu, i.p., for 30 days), corresponding to twice the recommended daily dose of copper. In the second phase, rats were divided into four groups: control (saline, i.p., water by gavage), copper (Cu, i.p., water by gavage), losartan (saline, i.p., 10 mg/kg/day losartan by gavage), or copper + losartan (Cu, i.p., 10 mg/kg/day losartan by gavage). After euthanasia, mesenteric PVAT was collected for morphometric analysis, gene and protein expression of adipokines, inflammatory molecules, and the renin-angiotensin system. Serum was used for hormone and biochemical measurements. Results: In mesenteric PVAT, chronic copper overload increased adipocyte diameter and reduced lipolysis. It also elevated the secretion of TNF-α and PAI-1 while decreasing IL-10 levels. Additionally, it upregulated the mRNA expression of MCP-1, F4/80, CD86, TLR4, arginase-1, iNOS, ACE1, and AT1R, alongside an increase in serum angiotensin II levels. When copper treatment was combined with losartan, an AT1R antagonist, adipocyte hypertrophy; TNF-α secretion; and the gene expression of TLR4, F4/80, and arginase-1 were attenuated. Conclusions: Chronic exposure to double the recommended dose of Cu disrupts the secretory function of mesenteric PVAT, promoting inflammation and altering the local RAS. These effects appear to occur, at least in part, alongside the activation of the AT1R-TLR4-angiotensin II signaling pathway, triggering the upregulation of vasoregulatory inflammatory markers.

Women with a history of preeclampsia (hxPE) have a ≥4-fold risk for developing cardiovascular disease (CVD) compared with women who had a healthy pregnancy (hxHC). HxPE have exaggerated vasoconstrictor sensitivity to angiotensin (ang) II after pregnancy, which likely contributes to CVD progression after preeclampsia. Ang II-mediated constriction via ang II type 1 receptors (AT1R) is countered by vasodilatory ang II type 2 receptors (AT2R); however, the extent to which reductions in AT2R-mediated responses contribute to exaggerated ang II-mediated constriction after preeclampsia remains unknown. We examined the balance of AT1R- and AT2R-mediated responses in hxPE and hxHC (n=12/group). We hypothesized that (1) attenuated AT2R-mediated dilation would be improved with AT1R inhibition in hxPE, and (2) AT2R inhibition would increase ang II-mediated constriction in hxHC but have no effect in hxPE. We measured cutaneous vascular conductance responses to compound 21 (AT2R agonist; 10-14–10-8mol/L) alone or with losartan (AT1R antagonist; 43 μmol/L) to assess AT2R-mediated dilation, and ang II (10−20–10−4 mol/L) alone or with PD-123319 (AT2R antagonist; 1 μmol/L) to assess the role of AT2R in vasoconstrictor sensitivity to ang II. Reduced AT2R-mediated dilation in hxPE (P=0.002) was improved with AT1R inhibition (P<0.001). Vasoconstrictor sensitivity to ang II was greater in hxPE compared with hxHC (P<0.001). Circulating AT1R agonistic autoantibodies (AT1-AA) were elevated in hxPE (P=0.015). AT2R inhibition increased the vasoconstrictor response to ang II in hxHC (P<0.001) but had no effect in hxPE (P=0.19). These data suggest that hxPE has reduced AT2R-mediated dilation that contributes to increased ang II vasoconstrictor sensitivity after preeclampsia.