Pulmonary arterial hypertension (PAH) is a cardiovascular disorder characterized by elevated pulmonary artery pressure as a result of arterial wall thickening. Patients are 3-4 times more likely to be women than men. This gender discrepancy demonstrates a need for an animal model with similar sex differences. 4,4'-Methylenedianiline (DAPM) is an aromatic amine used industrially in the synthesis of polyurethanes. Chronic, intermittent treatment of male and female rats with DAPM resulted in medial hyperplasia of pulmonary arterioles, exclusively in females, coupled to increases in pulmonary arterial pressures. Significant increases in plasma levels of endothelin-1 (ET-1) and serotonin, but decreases in nitrite [Formula: see text], were observed in females treated with DAPM. A decrease was observed in the serum ratio of the estrogen metabolites 2-hydroxyestradiol (2-OHE1)/16α-hydroxyestrogen (16α-OHE1). In females, ET-1,[Formula: see text] , and 2-OHE1/16α-OHE1 were significantly correlated with peak pressure gradient, an indirect measure of pulmonary arterial pressure. Expression of the serotonin transport protein (SERT) was significantly higher in the arteries of DAPM-treated females. In vitro, DAPM induced human pulmonary vascular smooth muscle cell proliferation and serotonin uptake, both of which were inhibited by treatment with the estrogen receptor antagonist ICI 182,780 or the selective serotonin reuptake inhibitor fluoxetine. DAPM also induced the release of serotonin from human pulmonary endothelial cells in culture, which is blocked by ICI 182,780. Taken together, this suggests that DAPM-mediated dysregulation of serotonin transport is estrogen-receptor dependent. Thus, DAPM-induced PAH pathology may be a new tool to clarify the sex selectivity of PAH disease pathogenesis.

Protandim is a dietary supplement with potent antioxidant properties. We hypothesized that Protandim would inhibit malignant progression of ductal carcinoma in situ (DCIS). A pre‐malignant human breast cancer cell line (MCF10DCIS.com) was grown in collagen type I for 1 week and then cultured for 2 more weeks in the presence or absence of a growth factor (GF) combination of TGF‐beta and CXCL12, 20ng/mL each. In the presence of GF, most cells exhibited long processes and formed interlacing networks and stellate aggregates. Numerous genes and cytokines involved in cancer progression, inflammation, and differentiation were up‐regulated. Bipotency was verified by IHC for pancytokeratin and alpha smooth muscle actin. Additional groups were dosed with 4‐hydroxytamoxifen (2.5 micromolar), Protandim (8 micrograms/mL), or vehicle (0.1% DMSO). In the Protandim and 4‐hydroxytamoxifen groups, more cells displayed a rounded shape with fewer processes. In the cytokine array, the following decreases by Protandim and 4‐hydroxytamoxifen (respectively) were observed: platelet‐derived growth factor (PGDF): 55% & 27%; interleukin 5 (IL‐5): 81% & 76%; monocyte chemotactic protein1 (MCP‐1): 84% & 76%; angiogenin: 68% & 77%; granulocyte‐macrophage colony‐stimulating factor (GM‐CSF): 63% & 44%; interleukin 6 (IL‐6): 77% & 79%. These results suggest Protandim may suppress DCIS progression. (NIH/NCRR)