Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence

Abstract

In an aging population, intense interest has shifted toward prolonging health span. Mounting evidence suggests that cellular reactive species are propagators of cell damage, inflammation, and cellular senescence. Thus, such species have emerged as putative provocateurs and targets for senolysis, and a clearer understanding of their molecular origin and regulation is of paramount importance. In an inquiry into signaling triggered by aging and proxy instigator, hyperglycemia, we show that NADPH Oxidase (NOX) drives cell DNA damage and alters nuclear envelope integrity, inflammation, tissue dysfunction, and cellular senescence in mice and humans with similar causality. Most notably, selective NOX1 inhibition rescues age-impaired blood flow and angiogenesis, vasodilation, and the endothelial cell wound response. Indeed, NOX1i delivery in vivo completely reversed age-impaired hind-limb blood flow and angiogenesis while disrupting a NOX1-IL-6 senescence-associated secretory phenotype (SASP) proinflammatory signaling loop. Relevant to its comorbidity with age, clinical samples from diabetic versus nondiabetic subjects reveal as operant this NOX1-mediated vascular senescence and inflammation in humans. On a mechanistic level, our findings support a previously unidentified role for IL-6 in this feedforward inflammatory loop and peroxisome proliferator–activated receptor gamma (PPARγ) down-regulation as inversely modulating p65-mediated NOX1 transcription. Targeting this previously unidentified NOX1-SASP signaling axis in aging is predicted to be an effective strategy for mitigating senescence in the vasculature and other organ systems.

An Olive Oil Mill Wastewater Extract Improves Chemotherapeutic Activity Against Breast Cancer Cells While Protecting From Cardiotoxicity

“…IL-6 accounts as a relevant cytokine in the inflammatory process ( 50 ) and is highly represented in the cytokine milieu characterizing the SASP phenotype ( 51 , 52 ). In line with this evidence, we found that HCMs treated with 5-FU, have increased transcript levels of IL-6 and the senescence marker p16.…”

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction

“…NOX enzymes are expressed in all cell types of the vasculature including the coronary vessels supplying blood to the heart [ 36 , 37 , 38 ]. Vascular NOX-generated ROS play essential roles in cardiovascular oxidative stress, aging, atherosclerosis, angiogenesis, inflammation, and blood pressure homeostasis [ 36 , 37 , 118 , 119 , 120 , 121 ]. Crosstalk between NOX enzymes and redox signaling pathways in the coronary vasculature, fibroblasts, and immune cells of the heart are likely involved in coronary microvascular dysfunction, inflammation, and myocardial relaxation defects in HFpEF ( Figure 1 ).…”

The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity

“…Compared to aortas from young mice (3 months), aortas from aged mice (18 months) had three-fold suppressed endothelial sprouting. When aged arteries were treated with NoxA1ds, a putative activation domain of NOX1 activator subunit, NOXA1, the arteries displayed restored endothelial sprouting [ 81 ]. Taken together, NOX1-generated ROS promote pathologic angiogenesis and may also inhibit reparative angiogenesis ( Figure 2 ).…”

“…NOX4 is involved in VEGF-mediated activation of VEGFR2 and downstream signaling of STAT3 and ERK1/2 to promote physiologic vascularization in the retina [ 85 ]. NOX1-generated ROS prevent reparative angiogenesis in response to senescence [ 81 ], and NOX2-generated ROS downregulate STAT3-dependent VEGF expression and prevent placental angiogenesis [ 86 ]. Regarding pathologic angiogenesis, NOX1- and NOX2-generated ROS contribute to tumor growth [ 78 , 79 , 87 ].…”