Cardiac hypertrophy and expression of the natriuretic peptide system in genetic models of heme oxygenase-1

Abstract

Objective: Heme oxygenase-1 (HO-1) has been well established as a cytoprotective molecule, and has been shown to exert cardioprotective effects in both hypertension and cardiac hypertrophy. However, the precise mechanism of the cardioprotective effect of HO-1 has yet to be fully elucidated. The natriuretic peptide system (NPS) is also a key player in cardiovascular homeostasis and tissue dynamics, and has also been shown to be cardioprotective in a variety of pathologic conditions. This study examined the effect of high dietary salt treatment in genetic models of HO-1, and assessed the expression of the NPS in the left ventricle (LV), in order to gain insight into the relationship between varying levels of HO-1 expression with the development of cardiac hypertrophy and the expression of the NPS. Methods: Age-matched 12-week old male HO-1 knockout (HO-1-/-) and HO-1 cardiomyocyte-specific transgenic overexpressing (HO-1Tg) mice were treated with either normal salt (NS; 0.8%) or high salt (HS; 8.0%) chow for 5 weeks. LV mRNA expression was determined using quantitative real-time RT-PCR. Results: HO-1-/- mice fed HS diet had significantly higher left ventricle-to-body weight ratio (LV/BW) compared to HO-1+/+ mice fed NS diet. HO-1-/- mice had significantly reduced expression of the NPS compared to controls, and these mice did not exhibit a salt-induced increase in ANP expression. HS treatment had no effect on LV/BW in HO-1Tg mice compared to controls. HO-1Tg mice had significantly higher ANP and BNP expression compared to controls. Conclusions: The presence of HO-1 is required for normal salt-induced changes in the local cardiac NPS. HO-1 ablation resulted in significantly lower mRNA expression of the NPS, whereas HO-1 overexpression resulted in higher mRNA expression of the NPS. These data indicate that the detrimental effect of reduced HO-1 expression and the cardioprotective effect of increased HO-1 expression may be due, in part, to altered expression of the NPS.