New insights into pulmonary arterial hypertension: interaction between PANoptosis and perivascular inflammatory responses

Abstract

Pulmonary arterial hypertension (PAH) is a heterogeneous disease characterized by various etiologies, with pulmonary vascular remodeling recognized as a main pathological change. Currently, it is widely accepted that vascular remodeling is closely associated with abnormal pulmonary vascular cell death and perivascular inflammation. The simultaneous activation of various pulmonary vascular cell death leads to immune cell adhesion and inflammatory mediator releases; And in turn, the inflammatory response may also trigger cell death and jointly promote the progression of vascular remodeling. Recently, PANoptosis has been identified as a phenomenon that describes the simultaneous activation and interaction of multiple forms of programmed cell death (PCD). Therefore, the relationship between PANoptosis and inflammation in PAH warrants further investigation. This review examines the mechanisms underlying apoptosis, necroptosis, pyroptosis, and inflammatory responses in PAH, with a focus on PANoptosis and its interactions with inflammation. And it aims to elucidate the significance of this emerging form of cell death and inflammation in the pathophysiology of PAH and to explore its potential as a therapeutic target.

Keywords: Apoptosis; Inflammation; Necroptosis; PANoptosis; Pulmonary artery hypertension; Pyroptosis.

Fig. 1

Pathophysiological mechanisms of PAH. Vascular remodeling is the critical pathophysiological mechanism in PAH, and is primarily composed of abnormal proliferation, death of pulmonary vascular cells, and peripheral vascular inflammation. The peripheral vasculature is primarily formed by various immune cells that release inflammatory mediators and chemokines via partially regulated factors. The abnormal death of pulmonary vascular cells mainly involves apoptosis resistance, pyroptosis, and necroptosis. Apoptosis was proposed in 1972, pyroptosis was officially named in 2001, and necroptosis was discovered in 2005. As of 2019, a total of five types of PANoptosis have been identified. This diagram was drawn by Figdraw (www.figdraw.com)

Fig. 2

Crosstalk between apoptosis, necroptosis, and pyroptosis at the molecular level. Pyroptosis is primarily mediated by inflammasomes, which ultimately lead to the cleavage of GSDMD and the release of IL-1β and IL-8. Apoptosis is activated by casp-3/7, and its activation can be induced by the apoptosome formed through Bax/BAK/Cyt or stimulated by FADD/casp-8. It can also mediate cleavage of GSDME, triggering pyroptosis. Necroptosis is mainly mediated by necrosomes that are composed of RIPK3 and MLKL. Additionally, FADD/casp-8 can form complex II by binding to RIPK1.When casp-8 is inhibited, complex II binds to RIPK3 to form necrosomes, thereby inducing necroptosis. This diagram was drawn by Figdraw (www.figdraw.com)

Fig. 3

Composition of the PANoptosome. When the ZBP1 PANoptosome is activated by IAV stimulation, it induces the occurrence of PANoptosis. It can be divided into two categories: one is composed of ZBP1, RIPK1, RIPK3, casp-8/6/3, and NLRP3, where NLRP3 mediates the release of IL-1β/18; the other category lacks NLRP3 and is unable to produce inflammatory factors. The RIPK1 PANoptosome consists of ASC, RIPK3, RIPK1, casp-1/8, and NLRP3, and is activated by Yersinia. The AIM2 PANoptosome is composed of AIM2, Pyrin, ZBP1, ASC, casp-1/8, RIPK3, RIPK1, and FADD, and is activated by HSV-1 and F.novicida. This diagram was drawn by Figdraw (www.figdraw.com)

Fig. 4

Composition of the PANoptosome. The NLRP12 PANoptosome is induced by TLR2/4 and is composed of NLRP12, ASC, casp-8, and RIPK3. The NLRC5 PANoptosome is induced after stimulation by TLR2/4 or mitochondrial damage, and consists of NLRC5, NLRP12, NLRP3, casp-8, ASC, and RIPK3. This diagram was drawn by Figdraw (www.figdraw.com)

Fig. 5

Relationship between PANoptosis and PAH. The activation of abnormal cell death in pulmonary vascular cells (ECs, SMCs, and fibroblasts) is one of the causes of vascular remodeling. Typical deaths include apoptosis resistance/apoptosis, pyroptosis, and necroptosis, whereas PANoptosis exhibits morphological changes characteristic of the above three. Furthermore, vascular remodeling can be associated with PANoptosis through the regulation of certain factors, including mitochondria-related components such as cGAS/STING, TAK1, Drp1, and FUNDC1, as well as immune-related factors such as HMGB1, Interferon regulatory factor-1 (IRF1), and miR-29a-3p. This diagram was drawn by Figdraw (www.figdraw.com)