Abstract 395: Heme Oxygenase-1-mediated PPARd Improves Cardiac Fibrosis and Inflammation in SCID Mice via Induction of T Reg Cells

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Introduction: Post-infarcted cardiac failure is the consequence of pathological remodeling after myocardial infarction (MI). A subtype of T lymphocytes, regulatory T (Treg) cells play an important role in improving cardiac function after MI via inhibition of inflammation and direct protection of cardiomyocytes. Heme oxygenase (HO)-1 induction improves heart function after ischemic damage by its anti-inflammatory, anti-oxidative and anti-fibrotic effects. To assess the role of Treg cells in post infarcted myocardium and on renal arteriolar vasoconstriction in immunosuppressed mice via the interplay of HO-1-PPAR δ axis.

Methods: We examined the effect of HO-1 induction on post-ischemic heart failure induced by left anterior descending coronary artery ligation, in T-lymphocyte immunosuppressive (BALB SCID) mice. Mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with the HO-1 inducer cobalt protoporphyrin (CoPP) with and without the HO activity inhibitor stannous mesoporphyrin (SnMP). Thirty days after surgery all mice underwent cardiac and renal Doppler sonography. Cardiac fibrosis and necrosis were analyzed and densitometry analysis of HO-1, PPAR δ and thromboxane synthase (TxA2) in cardiac tissues was done.

Results: Mice with MI had increased levels of cardiac fibrosis and necrosis (p<0.05) compared to sham operated controls. Echocardiography showed that fractional area shortening (FAS) was increased in the CoPP−MI group compared to the MI group (p<0.01). Renal pulsatiltiy index was increased in the MI group compared to the sham operated group (sham 0.72 ±0.08, MI 1.37±0.37, p<0.05). CoPP improved renal vasoconstriction as compared to the MI group (p<0.05). Increased expression of HO-1, PPAR-δ, pAMPK and pAKT and decreased expression of TxA2 was detected in cardiac tissues in CoPP-treated animals (p<0.02) as compared to the MI group. All these beneficial effects were reversed by SnMP.

Conclusion: Upregulation of HO-1 attenuates post myocardial fibrosis and inflammation and renal vasoconstriction in immunosuppressed mice via recruitment of Treg lymphocytes and PPAR delta activation.

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