Facchi, C. | Search bioRxiv

bioRxiv2025

Regional Vulnerability of Cardiac Chambers to Radiotherapy: A Multi-Omics Perspective

The heart is highly vulnerable to radiotherapy (RT)-induced injury, leading to molecular and structural remodeling collectively termed radiation-induced cardiac toxicity (RICT). Although several biological pathways have been implicated, the regional, cardiac-specific molecular responses to radiation exposure remain incompletely understood. Here, a multi-omics approach was adopted to longitudinally characterise the unique responses to radiation of the heart base (including ventricular base and right atrium), or the heart apex. Ventricular base irradiation induced a cardiomyopathy phenotype, with pronounced molecular perturbations in metabolism and electrical conduction, while changes related to tissue structure were predominant following apex-directed RT. In the right atrium, irradiation drives fibrotic tissue remodelling, leading to an increased propensity for atrial fibrillation, underpinned by changes in sarcomere organisation. This study represents a comprehensive characterisation of differential spatiotemporal radiation effects in the heart and highlights biological and functional pathways that are potentially clinically actionable for cardiac radioprotection and monitoring.

cell biology↗

bioRxiv2020

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

Arterial medial calcification is an independent risk factor for mortality in chronic kidney disease. We previously reported that knock-down of PKC expression increases high phosphate-induced mineral deposition by vascular smooth muscle cells in vitro. This new study tests the hypothesis that PKC regulates uremia-induced medial calcification in vivo. Female wild-type and PKC-/- mice underwent a two-stage subtotal nephrectomy and were fed a high phosphate diet for 8 weeks. X-ray micro computed tomography demonstrated that uremia-induced medial calcification was increased in the abdominal aorta and aortic arch of PKC-/- mice compared to wild-types. Blood urea nitrogen was also increased in PKC-/- mice compared to wild-types; there was no correlation between blood urea nitrogen and calcification in PKC-/- mice. Phosphorylated SMAD2 immunostaining was detected in calcified aortic arches from uremic PKC-/- mice; the osteogenic marker Runx2 was also detected in these areas. No phosphorylated SMAD2 staining were detected in calcified arches from uremic wild-types. PKC knock-down increased TGF-{beta}1-induced SMAD2 phosphorylation in vascular smooth muscle cells in vitro, whereas the PKC activator prostratin decreased SMAD2 phosphorylation. In conclusion, loss of PKC increases uremia-induced medial calcification. The PKC/TGF-{beta} signaling axis could therefore represent a new therapeutic target for arterial medial calcification in chronic kidney disease.

cell biology↗