Biology subjects

Redondo, J. M.

Publications and source records attributed to Redondo, J. M..

3 recordsLinked to original sources

bioRxiv2024

Integrated Stress Response Triggered by Excessive Glycosylation Drives Thoracic Aortic aneurysm

Thoracic aortic aneurysms and dissections (TAAD) are marked by degenerative changes in the aortic media. Marfan syndrome is the most common inherited connective tissue disorder associated with TAAD. While vascular smooth muscle cell (VSMC) metabolism is emerging as a targetable driver of aortic aneurysm, surgical interventions remain the primary strategy to prevent aortic dissection. Our research indicates that the hexosamine biosynthetic pathway (HBP), a branch of glycolysis, is upregulated in aortas from the Fbn1C1041G/+ Marfan Syndrome mouse model. Enhancing HBP activity promotes aortic dilation and accumulation glycan-rich extracellular matrix, contributing to aortic medial degeneration in wild-type mice. Mechanistically, fueling HBP activity induces VSMC dysfunction through excessive glycosylation, which activates the Integrated Stress Response (ISR). Pharmacological inhibition of HBP, along with ISR inhibition, successfully reverses aortic dilation and aortic medial degeneration in Fbn1C1041G/+ Marfan Syndrome mouse model. Additionally, Marfan Syndrome patients show elevated levels of HBP metabolites in blood plasma and serum, and heightened HBP-ISR signaling in patients with TAAD. These findings unveil a potential causative role for the HBP-ISR axis in medial degeneration in human TAAD, underscoring the need for evaluating HBP and ISR pathway as novel biomarkers and therapeutic strategies for thoracic aortic aneurysm.

molecular biology↗

bioRxiv2023

Phosphatase-independent activity of smooth-muscle calcineurin orchestrates a gene expression program leading to hypertension

STRUCTURED ABSTRACTObjective: Angiotensin-II (Ang-II) drives pathological vascular wall remodeling in hypertension and abdominal aortic aneurysm (AAA). Previous studies showed that the phosphatase activity of calcineurin (Cn) mediates Ang-II-induced AAA, but the cell type involved in the action of Cn in AAA formation remained unknown. Methods: Smooth muscle cell (SMC)-specific and endothelial cell (EC)-specific Cn-deficient mice (SM-Cn-/- and EC-Cn-/- mice, respectively) were created and assessed for Ang-II-induced AAA formation and hypertension vs controls. Osmotic minipumps were used to administer Ang-II and cyclosporine A (CsA), a pharmaceutical Cn inhibitor. AAA formation and hypertension were monitored by ultrasonography, arterial blood pressure monitoring, and histological analysis. Deep RNA sequencing was used to identify the Ang-II-regulated transcriptome sensitive to Cn deletion or pharmacological inhibition. Arterial and SMC contractility were also assessed. Results: Cn expressed in SMCs, but not ECs, was required for Ang-II-induced AAA. Unexpectedly, SMC Cn played a structural role in the early onset and maintenance of Ang-II-induced hypertension independently of Cn phosphatase activity. Nearly 90% of the genes regulated by Ang-II in the aorta required Cn expression in SMCs. Cn orchestrated, independently of its enzymatic activity, the induction by Ang-II of a gene expression program closely related to SMC contractility and hypertension. Cn deletion in SMCs, but not its pharmacological inhibition, impaired the regulation of arterial contractility. Among the genes whose regulation by Ang-II required Cn expression but not its phosphatase activity, we discovered that Serpine1 was critical for Ang-II-induced hypertension. Indeed, pharmacological inhibition of PAI-1, the protein encoded by Serpine1, impaired SMCs contractility and readily regressed hypertension. Conclusions: Whereas the phosphatase activity of Cn mediates Ang-II-induced AAA, a phosphatase-independent action of SMC Cn mediates hypertension by orchestrating a gene expression program closely related to contractility and blood pressure regulation. Our results urge the evaluation of PAI-1 as a candidate therapeutic target for hypertension.

pathology↗

bioRxiv2020

miR-203 imposes an intrinsic barrier during cellular reprogramming by targeting NFATC2

Cellular reprogramming from somatic to pluripotent cells is the basis for multiple applications aimed to replace damaged tissues in regenerative medicine. However, this process is limited by intrinsic barriers that are induced in response to reprogramming factors. In this manuscript we report that miR-203, a microRNA with multiple functions in differentiation and tumor suppression, acts as an endogenous barrier to reprogramming. Genetic ablation of miR-203 results in enhanced reprogramming whereas its expression prevents the formation of pluripotent cells both in vitro and in vivo. Mechanistically, this effect correlates with the direct repression of NFATC2, a transcription factor involved in the early phases of reprogramming. Inhibition of NFATC2 mimics miR-203 effects whereas NFATC2 overexpression rescues inducible cell pluripotency in miR-203-overexpressing cultures. These data suggest that miR-203 repression may favor the efficiency of reprogramming in a variety of cellular models.

cell biology↗