Intermedin 1-53 Ameliorates Atrial Fibrosis and Reduces Inducibility of
Atrial Fibrillation via TGF-β1/pSmad3 and Nox4 Pathways in a Rat Model
of Heart Failure



Heart failure was induced by MI in rats. Two weeks after MI surgery, rats
with large infarcts (40%) were randomized into control (untreated MI group, n=10) and IMDtreated (n=10) groups. The MI group and Sham group received saline injections. Rats in the IMD
group received IMD1-53, 10nmol/kg/day, intraperitoneally, for four weeks. The AF inducibility
and atrial effective refractory period (AERP) were assessed with the electrophysiology test. Additionally, the left atrial diameter and heart function and hemodynamic test were performed. We detected the area changes of myocardial fibrosis in the left atrium by using Masson staining. To detect the protein expression and mRNA expression of transforming growth factor-β1 (TGF-β1), αSMA, collagen Ⅰ, collagen Ⅲ and NADPH oxidase (Nox4) in myocardial fibroblasts and left atrial,
we used the Western blot method and the SYBR Green I real-time quantitative polymerase chain
reaction (PCR) assay



Compared with the MI group, IMD1-53 treatment decreased left atrial diameter and improved cardiac function, and it also improved the left ventricle end-diastolic pressure (LVEDP).
IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the
IMD group. In vivo, IMD1-53 reduced the left atrial fibrosis content in the heart of MI rats and inhibited mRNA and protein expression of collagen type Ⅰ and Ⅲ. IMD1-53 also inhibited the expression of TGF-β1, α-SMA and Nox4 both in mRNA and protein. In vivo, we found that IMD1-53
inhibited the phosphorylation of Smad3. In vitro, we found that the down-regulation of the expression of Nox4 was partly dependent on the TGF-β1/ALK5 pathway.



IMD1-53 reduced the inducibility and duration of AF and atrial fibrosis in the rats
after the MI operation. The possible mechanisms are associated with the inhibition of TGFβ1/Smad3-related fibrosis and TGF-β1/Nox4 activity. Therefore, IMD1-53 may be a promising
agent as upstream therapy for the prevention of AF.



Compared with the MI group, IMD1-53 treatment decreased left atrial diameter and improved cardiac function, it also improved the left ventrical end diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, the results showed that IMD1-53 reduced the left atrial fibrosis content on the heart of MI rats and inhibited the expression of collagen type Ⅰ and Ⅲ both in mRNA and protein. IMD1-53 also inhibited the expression of TGF-β1, α-SMA and Nox4 both in mRNA and protein. In vivo, the study also showed that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the down-regulated the expression of Nox4 was partly dependent on TGF-β1/ALK5 pathway.



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