The role of pro-inflammatory macrophage activation in cardiovascular disease (CVD) is a complex one amenable to network approaches. While an indispensible tool for elucidating the molecular underpinnings of complex diseases including CVD, the interactome is limited in its utility as it is not specific to any cell type, experimental condition or disease state. We introduced context-specificity to the interactome by combining it with co-abundance networks derived from unbiased proteomics measurements from activated macrophage-like cells. Each macrophage phenotype contributed to certain regions of the interactome. Using a network proximity-based prioritization method on the combined network, we predicted potential regulators of macrophage activation. Prediction performance significantly increased with the addition of co-abundance edges, and the prioritized candidates captured inflammation, immunity and CVD signatures. Integrating the novel network topology with transcriptomics and proteomics revealed top candidate drivers of inflammation. In vitro loss-of-function experiments demonstrated the regulatory role of these proteins in pro-inflammatory signaling.

Summary Organ donor's age negatively influences graft survival of organs, increasing risk of complications. Aging occurs in both men and women; however, the menopause marks a decrease in sex hormones and a sudden increase in the process of vascular aging. We investigated sex hormones' influence on the lung inflammatory process induced by BD in female rats. Wistar rats were grouped as: female rats from high estradiol to heat period (non‐OVx) and ovariectomized (OVx) female rats. Ovariectomy was carried out 10 days before BD. BD was induced using intracranial balloon rapid inflation. Serum hormones and inflammatory mediators were quantified, leukocytes and platelets counted and lung samples were collected for RT‐PCR, immunohistochemical, and histological analysis. Female sex hormones and corticosterone were reduced 6 h after BD in non‐OVx group. The infiltration of leukocytes in female non‐OVx lungs was higher compared to OVx. G‐CSF, VEGF, and CINC‐1 were found increased in non‐OVx group serum in comparison to OVx. Lung mediators were increased in non‐OVx rats compared to controls. The acute reduction of sex hormones induced by BD appears to have a worse effect on lung inflammation than a reduction that has happened over a prolonged period of time, allowing a physiological adaptation prior to BD.

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