Senescence Alterations in Pulmonary Hypertension

Abstract

Cellular senescence is the arrest of normal cell division and is commonly associated with aging. The interest in the role of cellular senescence in lung diseases derives from the observation of markers of senescence in chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (IPF), and pulmonary hypertension (PH). Accumulation of senescent cells and the senescence-associated secretory phenotype in the lung of aged patients may lead to mild persistent inflammation, which results in tissue damage. Oxidative stress due to environmental exposures such as cigarette smoke also promotes cellular senescence, together with additional forms of cellular stress such as mitochondrial dysfunction and endoplasmic reticulum stress. Growing recent evidence indicate that senescent cell phenotypes are observed in pulmonary artery smooth muscle cells and endothelial cells of patients with PH, contributing to pulmonary artery remodeling and PH development. In this review, we analyze the role of different senescence cell phenotypes contributing to the pulmonary artery remodeling process in different PH clinical entities. Different molecular pathway activation and cellular functions derived from senescence activation will be analyzed and discussed as promising targets to develop future senotherapies as promising treatments to attenuate pulmonary artery remodeling in PH.

Keywords: SASP; pulmonary hypertension; senescence; senolytics.

Figure 1

Hallmarks of cellular senescence. A large number of cellular processes are involved in the development of senescence. These include: morphological changes and macromolecular damage; increased lysosomal compartment, which is characterized by the overexpression of β-Gal; chromatin reorganization, which includes senescence-associated heterochromatin foci (SAHF); irreversible cell cycle arrest, driven by the action of p16 and p21/p53 axes, depending on the senescence driver and the implementation of a secretory phenotype, known as senescent-associated secretory phenotype (SASP) and characterized by the release of matrix metalloproteinases (MMP), cytokines and extracellular vesicles. Although these markers are strongly associated with a senescent phenotype, they are not exclusive or essential for the development of the program (with the exception of cell cycle arrest).

Figure 2

Types of senescence. Cellular senescence may be triggered by two different mechanisms: Replicative senescence and premature senescence. Replicative senescence refers to the decrease in proliferation due to shortening of telomeres as a consequence of multiple cell division. While premature senescence occurs in response to various stress stimuli, such as DNA damage, oncogenes, ionizing radiation, or oxidative stress.

Figure 3

Mechanisms of cellular senescence. TGFβ activates the p21 and p16 pathway to stop the cell cycle, which induces senescence. The binding of IL-6 to its unique-receptor IL-6R triggers the homodimerization of GP130. This results in the phosphorylation of Janus kinases (JAK), which phosphorylate intracellular tyrosine residues that serve as docking sites for STAT3. JAK/STAT induces cell cycle arrest and causes the initial generation of reactive oxygen species (ROS), subsequent senescence, and senescence associated secretory phenotype (SASP) (expression of IL-1α, IL-1β, IL-6, CTGF, VEGF, TGFβ, and osteopontin). NOX4 and TNFα also induce ROS production. ROS can induce senescence and SASP through the p38MAPK/NF-κB/p53 pathway.

Figure 4

Pathways and inhibitors of cellular senescence. MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; NAC: N-acetyl cysteine; NF-κB: nuclear factor-kappa B; ROS: reactive oxygen species.