Interruption of perivascular and perirenal adipose tissue thromboinflammation rescues prediabetic cardioautonomic and renovascular deterioration.

The cardiovascular and renovascular complications of metabolic deterioration are associated with localized adipose tissue dysfunction. We have previously demonstrated that metabolic impairment delineated the heightened vulnerability of both the perivascular (PVAT) and perirenal adipose tissue (PRAT) depots to hypoxia and inflammation, predisposing to cardioautonomic, vascular and renal deterioration. Interventions either addressing underlying metabolic disturbances or halting adipose tissue dysfunction rescued the observed pathological and functional manifestations. Several lines of evidence implicate adipose tissue thromboinflammation, which entails the activation of the proinflammatory properties of the blood clotting cascade, in the pathogenesis of metabolic and cardiovascular diseases. Despite offering valuable tools to interrupt the thromboinflammatory cycle, there exists a significant knowledge gap regarding the potential pleiotropic effects of anticoagulant drugs on adipose inflammation and cardiovascular function. As such, a systemic investigation of the consequences of PVAT and PRAT thromboinflammation and its interruption in the context of metabolic disease has not been attempted. Here, using an established prediabetic rat model, we demonstrate that metabolic disturbances are associated with PVAT and PRAT thromboinflammation in addition to cardioautonomic, vascular and renal functional decline. Administration of rivaroxaban, a FXa inhibitor, reduced PVAT and PRAT thromboinflammation and ameliorated the cardioautonomic, vascular and renal deterioration associated with prediabetes. Our present work outlines the involvement of PVAT and PRAT thromboinflammation during early metabolic derangement and offers novel perspectives into targeting adipose tissue thrombo-inflammatory pathways for the management its complications in future translational efforts.

Periprostatic adipose tissue thromboinflammation triggers prostatic neoplasia in early metabolic impairment: Interruption by rivaroxaban.

AIMS: Prostate cancer is among the highest incidence malignancies in men with a prevalence rate increasing in parallel to the rising global trends in metabolic disorders. Whereas a sizeable body of evidence links metabolic impairment to negative prognosis of prostate cancer, the molecular mechanism underlying this connection has not been thoroughly examined. Our previous work showed that localized adipose tissue inflammation occurring in select adipose depots in early metabolic derangement instigated significant molecular, structural, and functional alterations in neighboring tissues underlying the complications observed at this stage. In this context, the periprostatic adipose tissue (PPAT) constitutes an understudied microenvironment with potential influence on the prostatic milieu. MAIN METHODS AND RESULTS: We show that PPAT inflammation occurs in early prediabetes with signs of increased thrombogenic activity including enhanced expression and function of Factor X. This was mirrored by early neoplastic alterations in the prostate with fibrosis, increased epithelial thickness with marked luminal cellular proliferation and enhanced formation of intraepithelial neoplasia. Significantly, interruption of the procoagulant state in PPAT by a 10-day anticoagulant rivaroxaban treatment not only mitigated PPAT inflammation, but also reduced signs of prostatic neoplastic changes. Moreover, rivaroxaban decreased the murine PLum-AD epithelial prostatic cell viability, proliferation, migration, and colony forming capacity, while increasing oxidative stress. A protease-activated receptor-2 agonist reversed some of these effects. SIGNIFICANCE: We provide some evidence of a molecular framework for the crosstalk between PPAT and prostatic tissue leading to early neoplastic changes in metabolic impairment mediated by upregulation of PPAT thromboinflammation.

Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue.

The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.