Title Page
Contents
ABBREVIATION 7
ABSTRACT 9
Ⅰ. Introduction 10
Ⅱ. Materials and Methods 12
2.1. Animals 12
2.2. Tail-cuff plethysmography 12
2.3. Transthoracic echocardiography 12
2.4. Histopathological analysis 13
2.5. Protein preparation and western blot analysis 13
2.6. RNA isolation and real-time qPCR analysis 14
2.7. Serum biochemical analysis 14
2.8. RNA-sequencing and analysis of transcriptome data 14
2.9. Statistical analysis 15
Ⅲ. Results 16
3.1. Combined treatment with Low-ARNI/SGLT2i prolongs the overall survival of acute doxorubicin-injected mice 16
3.2. Combined treatment with Low-ARNI/SGLT2i prolongs the overall survival of acute doxorubicin-injected mice 18
3.3. Combined treatment with Low-ARNI/SGLT2i attenuates doxorubicin-induced cardiotoxicity 20
3.4. Combined treatment with Low-ARNI/SGLT2i stimulates the secretion of heart-driven hormones to coordinate kidney function 22
3.5. Effects of combined treatment with Low-ARNI/SGLT2i on cardiac energy metabolism during doxorubicin-induced cardiac dysfunction 24
Ⅳ. Discussion 28
Ⅴ. Conclusions 32
Ⅵ. References 33
Ⅶ. Supplemental data 36
CURRICULUM VITAE 39
Figure 1. Survival gains and the hemodynamic effects of ARNI and SGLT2i treatment in acute doxorubicin-injected mice. (A) Schematic design of acute heart failure model (15 mg/kg i.p.).... 16
Figure 2. Recovery effects of Low-ARNI/SGLT2i treatment on doxorubicin-induced cardiac dysfunction. (A) Schema of chronic heart failure model (15 mg/kg total). (B) Representative... 20
Figure 3. Protective effects of ARNI and SGLT2i treatment on doxorubicin-induced cardiotoxicity. (A) Whole-heart photograph. (B) The ratio of heart weight to tibia length... 22
Figure 4. Effects of ARNI and SGLT2i treatment on heart-driven hormones in chronic doxorubicin-injected mice. (A) Plasma concentration of NT-proANP and (B) BNP 9 weeks after... 23
Figure 5. Effects of ARNI and SGLT2i treatment on cardiac energy metabolism in doxorubicin-induced cardiac injury. (A) GSEA plots associated with Low-ARNI/SGLT2i-treated... 28
List of Supplemental Data Figures
Supplemental Figure 1. Low-ARNI/SGLT2i treatment prevents body weight loss during acute doxorubicin administration. (A) Body weight changes over 6 days in the acute heart failure... 36
Supplemental Figure 2. Transcriptomic analysis during ARNI and SGLT2i treatment in the chronic doxorubicin model of heart failure. (A) Principal component scatter plot of... 36
Supplemental Figure 3. ARNI and SGLT2i treatment effects on glucose metabolism re-partitioning in chronic doxorubicin-injected mice. (A) Representative immunoblots of GLUT4,... 37