The Role of Cathepsins in Vascular Remodeling and Stiffness of Pulmonary Hypertension Associated with Systemic Lupus Erythematosus

The presence of pulmonary arterial hypertension (PAH) in SLE is associated with a poor prognosis and increased mortality. Studies suggested that patients with PAH associated with SLE received PAH target treatment to decrease the pulmonary arterial systolic pressure and significantly prolong the survival. Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, and caused by vascular stiffness and remodeling. Elastin is critical in conferring vascular distensibility and in suppressing abnormal vascular smooth muscle cell growth. Studies have shown that increase in cysteine protease cathepsins (potent elastase) lead to a decrease in tropoelastin and damage elastin during atherosclerosis. Interestingly, a Nature Review Rheumatology article in 2014 suggested that cathepsin S blockade specifically improves SLE and lupus nephritis. As such, regulation and inhibition of cathepsins may play a significant role in PAH-SLE. Nevertheless, the relationship between elastin and cathepsins in the progress of PAH arterial stiffness associated with SLE has not been clarified. At our laboratory preliminary results show that tropoelastin production is decreased and there is a high expression of cathepsin S in the lung of PAH animal model and female MRL/lpr (Lupus) mice. Therefore, we hypothesize that the induction of cathepsin S may lead to a reduction of tropoelastin and affect the development of PAH arterial stiffness associated with SLE. We propose studies to identify the relationship between cathepsins signaling and reduced elastin assembly, these investigations, can be expected to lead to the identification of new biomarkers associated with the progression of PAH-SLE related to elastin degradation and to novel avenues of treatment related to stabilizing or repairing elastic laminae by PAH animal model and female MRL/lpr (Lupus) mice. To better understand the mechanisms underlying the suppressive effects of cathepsin S inhibitor in vascular stiffness of PAH associated with SLE, this proposal addresses a hypothesis that (a) vascular remodeling progresses through regulation of cathepsin S in controlling PASMC proliferation and migration, and has an aim to (b) develop an antagonist of cysteine protease cathepsin S for treatment of PAH associated with SLE based on the data obtained. This study investigates the following aims. (1) Understand the regulation of cathepsins in the cellular and molecular level to stimulate the proliferation and migration of PASMC on PAH development. (2) Identify if tropoelastin are impaired in SMC of PAH, cathepsin S inhibitor can prevent the damage of assembled elastin and reduce the proliferation, migration, and dedifferentiation of PASMCs in vitro. (3) Understand if cathepsin S inhibitor can suppress pulmonary vascular stiffness and remodeling in monocrotaline-treated rats and female MRL/lpr (Lupus) mice in vivo. The execution of these studies will provide a deeper understanding of the pathogenesis of PAH-SLE. The results may serve to define the role of cathepsins in preventing progressive and fatal SLE-PAH, and provide innovative approaches for therapeutic interventions in SLE-PAH.

Project ID:PC10601-0357
External Project ID:MOST104-2314-B182-020-MY3