Abstract 18849: Arterial Calcification Can Be Inhibited via Maintained Mitochondrial Homeostasis in Chronic Kidney Disease

Background: Vascular calcification (VC) is a significant contributor to cardiovascular mortality in patients with chronic kidney disease and chronic inflammatory conditions. Previous work by our group has shown that HSP72 is an inducible protein that can preserve mitochondrial complexes II, IV, NADH cytochrome c reductase (NCCR), succinate cytochrome c reductase (SCCR), and cytochrome c oxidase (CCO) activities and prevent cardiomyocyte apoptosis. We recently reported that heat shock protein 72 (HSP72) could be induced in human arteries and prevent human aortic smooth muscle cell (HA-SMC) calcification. However, the molecular mechanisms involved in vasculo-protective effects of HSP72 have yet to be elucidated. In this study, we postulate that inducible HSP72 may exert vasculo-protective effects by stabilizing HA-SMCs phenotype through inhibition of mitochondrial dysfunction. Methods: In vitro long-term calcification model: HA-SMCs treated with calcification medium (CM) containing 5mM CaCl 2 and 5mM β-glycerophosphate for 21 days. Results: Our results show that inducible HSP72 and mitochondrial HSP (HSPA5) are significantly expressed following heat shock treatment in HA-SMCs. Inducible HSP72 inhibited the development of VC in our long-term calcification model, in vitro . We next showed that JC-1 complex, an indicator of mitochondrial membrane potential stability and mitochondrial respiratory chain complexes II, IV was preserved in HA-SMCs treated with calcification medium following induction of HSP72. These cellular protective effects were however abolished following HSP72 knockdown by HSP72 siRNA. Furthermore, p53, Bax and Bak were up-regulated and Bcl-2 was down-regulated in HA-SMCs treated in calcification medium and these pro-apoptotic changes could be reversed following induction of HSP72. Conclusion: HSP72’s anti-calcific effects involve stabilization of mitochondrial function and inhibition of HA-SMC apoptosis. We suggest treatment strategies involving induction of HSP72 as a new approach to inhibit VC.