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Pituitary adenylate cyclase-activating polypeptide (PACAP) protects against mitoxantrone-induced cardiac injury in
Venkat Subramaniam1, Gin Chuang1, Huijing Xia2
1Department of Pharmacology and Experimental Therapeutics, Louisiana State University, Health Sciences Center, New Orleans, LA 70112-1393, United States.
Abstract:
Mitoxantrone (MXT) is an androstenedione that is used to treat cancers and progressive forms of multiple sclerosis; however, its use is limited by its cardiotoxicity. Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the secretin/growth hormone-releasing hormone/vasoactive intestinal peptide family and has many functions, including cytoprotection and immunosuppression. We tested the hypothesis that PACAP can protect against MXT-induced cardiotoxicity in mice. Female BALB/c mice were treated once weekly for 4 weeks with saline (n=14) or MXT (3mg/kg, i.p.; n=14). Half of the mice in each group received PACAP (10μg, i.p.) 1h before and 24 and 48h after MXT, while the remaining mice received injections of saline on the same schedule. Echocardiography was used to assess cardiac structure and function. In mice treated with MXT and saline, body weight was significantly reduced after the third dose of MXT. PACAP significantly attenuated the reduction in body weight; however, the weights did not return to control level. Compared to controls, MXT-treated mice had significantly increased left ventricular (LV) diameter and LV volume and decreased LV posterior wall thickness. Fractional shortening (FS) and ejection fraction (EF) were also significantly decreased. Treatment with PACAP prevented MXT-induced LV dilation and significantly attenuated the reductions in FS and EF, although FS and EF did not return to control level. PACAP38 did not prevent MXT-induced decreases in LV posterior wall thickness. MXT dose-dependently decreased the viability of cultured U937 (human leukemia) cells; PACAP did not protect cultured U937 cells from MXT-mediated cell death. In conclusion, PACAP can attenuate MXT-mediated LV dilation and dysfunction in mice.
Insights
Pituitary adenylate cyclase activating polypeptide (PACAP) helps protect against mitoxantrone (MXT)-induced heart damage in mice. PACAP attenuated MXT
Area of Science:
- Cardiology
- Pharmacology
- Oncology
- Neurology
Background:
- Mitoxantrone (MXT) is an effective anticancer and multiple sclerosis therapeutic, but its clinical use is limited by cardiotoxicity.
- Pituitary adenylate cyclase activating polypeptide (PACAP) exhibits cytoprotective and immunosuppressive properties.
- The potential of PACAP to mitigate MXT-induced cardiotoxicity remains unexplored.
Purpose of the Study:
- To investigate the protective effects of PACAP against MXT-induced cardiotoxicity in a murine model.
- To evaluate the impact of PACAP on cardiac structure and function in mice treated with MXT.
Main Methods:
- Female BALB/c mice received weekly MXT injections (3mg/kg) for 4 weeks.
- Mice were co-treated with PACAP (10μg) or saline at specific intervals relative to MXT administration.
- Cardiac structure and function were assessed using echocardiography; body weight and cell viability were also measured.
Main Results:
- MXT treatment led to significant reductions in body weight, increased left ventricular (LV) diameter and volume, and decreased LV posterior wall thickness.
- Fractional shortening (FS) and ejection fraction (EF) were significantly reduced in MXT-treated mice.
- PACAP administration attenuated MXT-induced body weight loss and prevented LV dilation, while significantly mitigating reductions in FS and EF.
Conclusions:
- PACAP demonstrates a protective effect against MXT-induced cardiotoxicity in mice, specifically by preventing LV dilation and mitigating systolic dysfunction.
- While PACAP attenuated cardiac dysfunction, it did not fully restore cardiac function to control levels or prevent MXT-induced decreases in LV posterior wall thickness.
- PACAP did not protect cultured U937 cells from MXT-mediated cytotoxicity, suggesting its protective effects are specific to the cardiac tissue in vivo.
