Sulforaphane Does Not Protect Right Ventricular Systolic and Diastolic Functions in Nrf2 Knockout Pulmonary Artery Hypertension Mice.

Abstract

PurposeNrf2 is a nuclear transcription factor and plays an important role in the regulation of oxidative stress and inflammation. We recently demonstrated that sulforaphane (SFN) protected mice from developing pulmonary arterial hypertension (PAH) and right ventricular (RV) dysfunction by elevating cardiac Nrf2 expression and function. Here we further investigate Nrf2 dependence for SFN-mediated prevention of PAH and RV dysfunction in an Nrf2 knockout mouse model.MethodsWe used male global Nrf2-knockout mice and male C57/6 J wild type mice in the following groups: Control group received room air and vehicle control; SuHx group received SU5416 and 10% hypoxia for 4 weeks to induce PAH; SuHx+SFN group received both SuHx and sulforaphane, a Nrf2 activator, for 4 weeks. Transthoracic echocardiography was performed to quantify RV function and estimate pulmonary vascular resistance over 4 weeks. PAH was confirmed using invasive RV systolic pressure measurement at 4 weeks.ResultsAll Nrf2 knockout mice survived the 4-week SuHx induction of PAH. SuHx caused progressive RV diastolic/systolic dysfunction and increased RV systolic pressure. The development of RV diastolic dysfunction occurred earlier in the Nrf2 knockout PAH mice when compared with the wide type PAH mice. SFN partially or completely reversed SuHx-induced RV diastolic/systolic dysfunction and increased RV systolic pressure in wild-type mice, but not in Nrf2 knockout mice.ConclusionOur findings demonstrated the essential role of Nrf2 in SFN-mediated prevention of RV dysfunction and PAH, and increasing Nrf2 activity in patients with PAH may have therapeutic potential.