Abstract 17150: Restoring Impaired L-Arginine Transport Can Attenuate Renal Fibrosis and Inflammation in a Mouse Model of Dilated Cardiomyopathy

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Abstract

Introduction: Heart failure (HF) is a complex pathophysiologic disorder, in which cardiac and renal fibrosis together with endothelial dysfunction are common features. We have previously demonstrated that impaired L-arginine transport contributes to diminished bioavailability of nitric oxide (NO). We tested the hypothesis that restoring L-arginine transport could exert beneficial cardiac and renal effects in HF.

Methods: Eighteen-week-old WT mice (n=8), transgenic mice with dilated cardiomyopathy (DCM;n=8) due to overexpression of the mammalian sterile 20-like kinase 1, and double transgenic mice with DCM and endothelial-specific overexpression of the L-arginine transporter cationic amino acid transporter 1 (Cat1) (HFCAT1;n=8) were used. Plasma nitrate/nitrite levels, cardiac and renal fibrosis, gene expression, structure and function were assessed.

Results: Plasma nitrate/nitrite was 78% lower in DCM mice than WT (P<0.05). This was restored in HFCAT1 mice to levels observed in WT. Cardiac interstitial and perivascular fibrosis were 89% and 45% greater respectively in DCM mice than WT (P<0.001). Tubulointerstitial and glomerular fibrosis were 89% and 76% greater respectively in DCM mice than WT (P<0.05). Cardiac and renal fibrosis were significantly attenuated in HFCAT1 mice compared to DCM mice (P<0.05). Consistent with this, renal mRNA expression of Il6 and Il1β were less in HFCAT1 mice than DCM (P<0.05). Renal mRNA expression of Il10 and Cat1 were 57% and 23% less in DCM mice than WT and these were restored in HFCAT1 mice (P<0.05). Cardiac mRNA expression of Il6 was 92% greater in DCM mice than WT and this was normalised in HFCAT1 mice (P<0.01). Mean LV wall thickness and ejection fraction were 23% and 33% less respectively in DCM mice compared to WT (P<0.01). Endothelial-specific overexpression of Cat1 in DCM mice had no effect on mean LV wall thickness and ejection fraction (P>0.24). Endothelial-specific overexpression of Cat1 in DCM mice also had no effect on renal function (P>0.98).

Conclusion: Augmenting L-arginine transport by increasing expression of Cat1 can attenuate renal fibrosis and inflammation in the setting of HF.

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