Cadmium-induced Pulmonary Arterial Hypertension Pathogenesis and Underlying Mechanisms

About This Grant

Prevalence of pulmonary arterial hypertension (PAH) is increasing worldwide with five-year survival <50%. There is no effective therapy to prevent right ventricular (RV) failure in PAH, urging the need to investigate its pathogenic mechanisms to develop novel preventive and therapeutic approaches. Experimental models and clinical data showed that oxidative stress appears as a significant mediator and predictor of worse outcomes in PAH. Noteworthy, exposures to nonessential metals, such as cadmium (Cd), have been linked to increased incidence of cardiovascular diseases. However, no study has investigated the association of chronic environmental exposure to Cd with PAH although some indirect findings available. Our preliminary metallomics data showed, when compared to controls, both lung and cardiac Cd levels significantly increased in male mice received 5 ppm Cd exposure in the drinking water for 12 weeks (wks). Pulmonary artery collagen accumulation and muscularization severity as one of the key pathogeneses in PAH worsened in the lung of mice exposed to 12-wks Cd, a PAH-like pathogenesis of mice with PAH induced by SuHx a well characterized rodent PAH model. Metallomics analysis revealed significant Fe accumulations in the lungs of Cd-exposed and SuHx-induced PAH mice. However, whether longer Cd exposure can induce or exacerbate PAH pathogenesis, and whether these can be replicated in female mice remain unknown. We thus hypothesize that chronic exposure to Cd at environmental levels for 16-wks can induce PAH or exacerbate SuHx-induced PAH pathogenesis, which is because Cd may cause iron dyshomeostasis and associated ferroptosis. Aim 1: To comprehensively define whether chronic Cd exposure can directly induce, and/or exacerbate PAH pathogenesis and essential metal homeostasis in the heart and lungs. We will have three groups, 1) Cd exposure model for 16 wks in both male and female mice; 2) Pre-PAH Cd model will be given Cd in the drinking water for 16 weeks meanwhile PAH will be induced with Su5416/hypoxia (SuHx) during the last 4 wks; 3) Post-PAH Cd model will be similar to group #2, except for PAH induction during the first 4 wks. For all 3 models, cardiac functions will be examined with echocardiography before and after PAH induction and every 4 weeks until the end of the 16-wk exposure. Mice will be euthanized at the end of 16 weeks to collect blood, lungs, and heart for PAH pathogenesis analysis. Aim 2: To define the mechanism of Cd-induced Fe redistribution and Fe-mediated ferroptosis in PAH pathogenesis. Aim 2a will analyze Cd and essential metals in the blood and tissues by metallomics, Fe metabolism related transporters and mediators, and lung and cardiac ferroptosis. Aim 2b will apply laser capture collection of pulmonary arteries from the lungs of mice with and without Cd collected in Aim 1, for proteomic analysis determining distinct protein expression profiles to reveal novel insights into mechanisms for Cd-caused Fe redistributions, ferroptosis, and signaling pathways. Aim 2c will define pathogenic roles of ferroptosis in PAH pathogenesis and RV dysfunction in vivo using ferroptosis inhibitor and Fe chelator in mouse models.