Acceleration of artery stiffness during childhood obesity in mice lacking lysosomal acid ceramidase

Childhood obesity imposes significant risks of cardiovascular diseases in adulthood and the late life. Our previous studies found that the arterial calcification was developed in Asah1 fl/fl /SM cre mice, a mouse model whose lysosomal acid ceramidase was tissue-specifically knocked out in smooth muscle cells. The present study was designed to investigate whether there occurred arterial stiffness, an early pathological event prior to the arterial calcification, and explore the underling mechanism in Asah1 fl/fl /SM cre mice at their young age. The young obesity mice were generated by starting with feeding mother mice with high fat diet (HFD) during their gestation and lactation, followed by putting pups on HFD for 6 weeks after weaning. The arterial stiffness was assessed in vivo by pulse wave velocity (PWV) method using the ultrasound to measure velocity of arterial waveform traveling along the aorta. It was found that PWV was significantly increased, an indication of elevated arterial stiffness, in young obese Asah1 fl/fl /SM cre mice than wild type mice. In the isolated aorta using wire and pressure myography, young obese Asah1 fl/fl /SM cre mice were found to have much steeper force-diameter curve from wire myography, but much smaller maximal increases in aorta diameter compared to WT controls in pressure myography. To explore the mechanisms accelerating arterial stiffness in young obese Asah1 fl/fl /SM cre , integrins level and their adhesion to fibronectin were examined. Immunohistochemistry showed that the aortic integrin staining significantly increased in the aorta from young obese Asah1 fl/fl /SM cre mice. Confocal microscopy demonstrated that the colocalization coefficient of integrin with fibronectin was also markedly enhanced in the aorta from young obese Asah1 fl/fl /SM cre mice. This increased integrin staining and integrin-fibronectin interactions were markedly attenuated when young obese Asah1 fl/fl /SM cre mice were treated with amitriptyline (a lysosomal function enhancer), rapamycin (a lysosomal function enhancer) or ML-SA5 (a lysosomal TRP-ML1 channel agonist). In primary cultures of aortic smooth muscle cells (ASMCs) from Asah1 fl/fl /SM cre mice, the recycling rates of integrin (labeled with Alexa 488 integrin antibody) to the cell membrane (stained with Alexa 594-wheat germ agglutinin) was shown markedly elevated in response to visfatin, compared to those ASMCs from WT mice. These results strongly suggest that the deficiency of lysosomal acid ceramidase accelerates arterial stiffness in young obese mice, which may be associated with enhanced integrin recycling back to cell membrane of ASMCs. Supported by NIH grants HL057244 and HL075316 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.