Session: 605. Molecular Pharmacology, Drug Resistance—Lymphoid and Other Diseases: Poster I
Hematology Disease Topics & Pathways:
Adverse Events, Clinically relevant
Methods: Ten young C57Bl/6 mice (12-14 weeks of age) and thirty aged C57Bl/6 mice (15-17 months of age) were randomly assigned as follows: (i) Control group [Normal Saline (N/S) 0.9%, n=6]; (ii) Cfz group (8 mg/kg, n=6); (iii) Met group (140mg/kg, n=6); (iv) Cfz+Met group (8 mg/kg and 140 mg/kg respectively, n=6). N/S and Cfz were administered intraperitoneally on alternate days, while Met was administered per os daily for 7 days. At baseline and at the end of the experiments, mice were anesthetized with isoflurane (2% in 100% O2) and underwent echocardiography in order to investigate cardiac contractility markers (fractional shortening, FS%) and carotid plasticity markers (pulsatility index, PI% and resistance index, RI%). Subsequently mice were sacrificed for blood and myocardial tissue collection. Peripheral blood mononuclear cell (PBMCs), isolated from the whole blood, as well as myocardial tissue underwent proteasome activity assessment. Snap-frozen myocardial tissue underwent molecular immunoblotting analysis for the investigation of the molecular signaling.
Results: Aged mice did not show any decreased proteasomal activity neither in the PBMCs or in the myocardium versus young C57Bl/6 mice. Cfz decreased proteasomal activity both in the PBMCs and the myocardium independently of Met administration. Aged mice presented a significant reduction of the FS% compared to the young mice at baseline, which represents an already established cardiac dysfunction in the elderly mice (mean FS%±SD: 37.40±1.6 vs. 45.62±0.8, respectively, p<0.005). In compliance with our previous findings in young C57Bl/6 mice, Cfz deteriorated the already present cardiac dysfunction in aged mice versus controls (mean FS%±SD: 28.2±1.8 vs. 37.8±1.8, respectively, p<0.05). Cfz+Met co-administration in elderly mice showed a marginal increase in terms of FS% compared to Cfz only treated mice (mean FS%±SD: 32.60±2.1 vs. 28.2±1.8, respectively), while FS% in the Cfz+Met group continued to be lower compared to control group (32.60±2.1 vs. 37.8±1.8). Assessment of the carotid stiffness revealed that Cfz sub-acute treatment led to a decrease in PI% compared to controls (p<0.05), while no changes in RI% were observed among groups, indicating a Cfz-induced vascular hypo-contraction in the elderly mice. Molecular analysis of the myocardial tissues showed that Cfz led to a decreased AMPKα and Protein Kinase B (Akt) phosphorylation, while Met restored AMPKα phosphorylation and increased endothelial nitric oxide synthase (eNOS) and Akt expression in the Cfz+Met co-administration group.
Conclusion: Cfz induced cardiotoxicity in this aged murine model, in accordance with our previous findings in the young mice. Additionally, sub-acute Cfz treatment leads to a decrease in pulsatility capacity of the vessels, possible leading to vascular hypo-contraction in vivo. Co-administration with metformin exerts cardioprotection, even in the elderly mice, in an AMPKα-dependent manner. The latter is of great clinical significance as it further supports the translational value of metformin as a potent prophylactic therapy against Cfz-induced cardiotoxicity.
Disclosures: Efentakis: Amgen: Research Funding. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Dimopoulos: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Andreadou: Amgen: Research Funding. Terpos: Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding.
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