CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice

CD38 is the main enzyme for nicotinamide adenine dinucleotide(NAD)degradation in mammalian cells.Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases.Our study showed that CD38 deficiency significantly alleviated angiotensin II(Ang ll)-induced vascular remodeling in mice,as shown by decreased blood pressures;reduced vascular media thickness,media-to-lumen ratio,and collagen deposition;and restored elastin expression.However,our bone marrow transplantation assay showed that CD38 deficiency in lymphocytes led to lack of protection against Ang ll-induced vascular remodeling,suggesting that the effects of CD38 on Ang ll-induced vascular remodeling might rely primarily on vascular smooth muscle cells(VSMCs),not lymphocytes.In addition,we observed that CD38 deficiency or NAD supplementation remarkably mitigated Ang ll-induced vascular senescence by suppressing the biogenesis,secretion,and internalization of senescence-associated small extracellular vesicles(SA-sEVs),which facilitated the senescence of neighboring non-damaged VSMCs.Furthermore,we found that the protective effects of CD38 deficiency on VSMC senescence were related to restoration of lysosome dysfunction,particularly with respect to the maintenance of sirtuin-mediated mitochondrial homeostasis and activation of the mitochondria-lysosomal axis in VSMCs.In conclusion,our findings demonstrated that CD38 and its associated intracellular NAD decline are critical for Ang ll-induced VSMC senescence and vascular remodeling.

Poly(I:C)preconditioning protects the heart against myocardial ischemia/reperfusion injury through TLR3/PI3K/Akt-dependent pathway

Emerging evidence suggests that Toll-like receptors(TLRs)ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion(I/R)injury.As the ligand of TLR3,polyinosinic-polycytidylic acid(poly(I:C)),a synthetic double-stranded RNA,whether its preconditioning can exhibit a cardioprotective phenotype remains unknown.Here,we report the protective effect of poly(I:C)pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway.Poly(I:C)pretreatment leads to a significant reduction of infarct size,improvement of cardiac function,and downregulation of inflammatory cytokines and apoptotic molecules compared with controls.Subsequently,our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced,and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C)pretreatment,while knock out of TLR3 suppresses the cardioprotection of poly(I:C)preconditioning through a decreased activation of PI3K/Akt signaling.Moreover,inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C)preconditioning-induced cardioprotective effect.In conclusion,our results reveal that poly(I:C)preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3,and the downstream PI3K/Akt signaling,which may provide a potential pharmacologic target for perioperative cardioprotection.