The cardioprotective effect of melatonin and exendin‐4 treatment in a rat model of cardiorenal syndrome

Abstract We investigated the cardioprotective effect of melatonin (Mel) and exendin‐4 (Ex4) treatment in a rat model of cardiorenal syndrome ( CRS ). Adult male SD rats (n=48) were randomly and equally divided into sham control ( SC ), dilated cardiomyopathy ( DCM ) (doxorubicin 7 mg/kg i.p. every five days/4 doses), CRS (defined as DCM + CKD ) only, CRS ‐Mel (20 mg/kg/d), CRS ‐Ex4 (10 μg/kg/d), and CRS ‐Mel‐Ex4 groups. In vitro results showed protein expressions of oxidative stress ( NOX ‐1/ NOX ‐2/oxidized protein), DNA /mitochondrial damage (γ‐H2 AX /cytosolic cytochrome c), apoptosis (cleaved caspase‐3/ PARP ), and senescence (β‐galactosidase cells) biomarkers were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/p‐cresol‐treated H9c2 cells that were revised by Mel and Ex4 treatments (all P <.001). By day 60, LVEF was highest in the SC and lowest in the CRS , significantly lower in the DCM than in other treatment groups, lower in the CRS ‐Mel and CRS ‐Ex4 than in the CRS ‐Mel‐Ex4, and lower in the CRS ‐Mel than in the CRS ‐Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all P <.001). Plasma creatinine level was highest in the CRS and lowest in the SC and progressively decreased from the CRS ‐Mel, CRS ‐Ex4, CRS ‐Mel‐Ex4 to DCM ( P <.0001). Protein expressions of inflammation ( TNF ‐α/ NF ‐κB/ MMP ‐2/ MMP ‐9/ IL ‐1β), apoptosis/ DNA damage (Bax/c‐caspase‐3/c‐ PARP /γ‐H2 AX ), fibrosis (Smad3/ TGF ‐β), oxidative stress ( NOX ‐1/ NOX ‐2/ NOX ‐4/oxidized protein), cardiac hypertrophy/pressure overload ( BNP /β‐ MHC ), and cardiac integrity (Cx43/α‐ MHC ) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all P <.001). Fibrotic area, DNA damage (γ‐H2 AX + /53 BP 1 + CD 90 + / XRCC 1 + CD 90 + ), and inflammation ( CD 14 + / CD 68 + ) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all P <.001). Combined melatonin and exendin‐4 treatment suppressed CRS ‐induced deterioration of LVEF and LV remodeling.