The NADPH oxidase (Nox) family of proteins is comprised of seven members, including Noxes1–5 and the Duoxes 1 and 2. Nox4 is readily distinguished from the other Nox isoforms by its high level of expression in cardiovascular tissues and unique enzymatic properties. Nox4 is constitutively active and the amount of reactive oxygen species (ROS) contributed by Nox4 is primarily regulated at the transcriptional level although there is recent evidence for post-translational control. Nox4 emits a different pattern of ROS and its subcellular localizations, tissue distribution and influence over signaling pathways is different from the other Nox enzymes. Previous investigations have revealed that Nox4 is involved in oxygen sensing, vasomotor control, cellular proliferation, differentiation, migration, apoptosis, senescence, fibrosis, and angiogenesis. Elevated expression of Nox4 has been reported in a number of cardiovascular diseases, including atherosclerosis, pulmonary fibrosis, and hypertension, cardiac failure and ischemic stroke. However, many important questions remain regarding the functional significance of Nox4 in health and disease, including the role of Nox4 subcellular localization and its downstream targets. The goal of this review is to summarize the recent literature on the genetic and enzymatic regulation, subcellular localization, signaling pathways, and the role of Nox4 in cardiovascular disease states.

A defining characteristic of Pulmonary Hypertension (PH) is the extensive remodeling of pulmonary arteries (PA) that results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMC) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, Western blotting and immunofluorescence imaging and its functional role was assessed by specific Gal-3 inhibitors and CRISPR-Cas9 mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMC which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.

Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature that involves the loss of endothelial function together with inappropriate smooth muscle cell growth, inflammation, and fibrosis. These changes underlie a progressive remodeling of blood vessels that alters flow and increases pulmonary blood pressure. Elevated pressures in the pulmonary artery imparts a chronic stress on the right ventricle which undergoes compensatory hypertrophy but eventually fails. How PAH develops remains incompletely understood and evidence for the altered production of reactive oxygen and nitrogen species (ROS, RNS respectively) in the pulmonary circulation has been well documented. There are many different types of ROS and RNS, multiple sources, and collective actions and interactions. This review summarizes past and current knowledge of the sources of ROS and RNS and how they may contribute to the loss of endothelial function and changes in smooth muscle proliferation in the pulmonary circulation.

Significance: Pulmonary arterial hypertension (PAH) is a progressive disease arising from the narrowing of pulmonary arteries (PAs) resulting in high pulmonary arterial blood pressure and ultimately right ventricle (RV) failure. A defining characteristic of PAH is the excessive and unrelenting inward remodeling of PAs that includes increased proliferation, inflammation, and fibrosis. Critical Issues: There is no cure for PAH nor interventions that effectively arrest or reverse PA remodeling, and intensive research over the past several decades has sought to identify novel molecular mechanisms of therapeutic value. Recent Advances: Galectin-3 (Gal-3) is a carbohydrate-binding lectin remarkable for its chimeric structure, composed of an N-terminal oligomerization domain and a C-terminal carbohydrate-recognition domain. Gal-3 has been identified as a regulator of numerous changes in cell behavior that contributes to aberrant PA remodeling, including cell proliferation, inflammation, and fibrosis, but its role in PAH has remained poorly understood until recently. In contrast, pathological roles for Gal-3 have been proposed in cancer and inflammatory and fibroproliferative disorders, such as pulmonary vascular and cardiac fibrosis. Herein, we summarize the recent literature on the role of Gal-3 in the development of PAH. We provide experimental evidence supporting the ability of Gal-3 to influence reactive oxygen species production, NADPH oxidase enzyme expression, and redox signaling, which have been shown to contribute to both vascular remodeling and increased pulmonary arterial pressure. Future Directions: While several preclinical studies suggest that Gal-3 promotes hypertensive pulmonary vascular remodeling, the clinical significance of Gal-3 in human PAH remains to be established. Antioxid. Redox Signal. 00, 000–000.