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Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo

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An Erratum to this article was published on 25 January 2013

Abstract

Sildenafil inhibits cyclic GMP-specific phosphodiesterase type-5A (PDE5A) and can prevent cardiac hypertrophy and left ventricular (LV) dysfunction in mice subjected to severe pressure-overload. The pathophysiological role of sildenafil in adverse remodeling in the hypertensive heart after chronic renin–angiotensin aldosterone system stimulation is unknown. Therefore, we studied the efficacy of the PDE5A inhibitor sildenafil for treating advanced cardiac hypertrophy and LV remodeling due to angiotensin (Ang)II-induced heart failure (HF) in vivo. C57BL6/J mice were subjected to AngII-induced cardiac hypertrophy for 3 weeks and cardiac dysfunction, cardiac inflammatory stress response, adverse remodeling as well as apoptosis were documented. Mice were subsequently treated with sildenafil (100 mg/kg/day) or placebo with delay of 5 days for treating AngII infusion-induced adverse events. Compared to controls, AngII infusion resulted in impaired systolic (dP/dt max −46 %, SV −16 %, SW −43 %, E a +51 %, EF −37 %, CO −36 %; p < 0.05) and diastolic (dP/dt min −36 %, LV end diastolic pressure +73 %, Tau +21 %, stiffness constant β +74 %; p < 0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased inflammatory response was also indicated by an increase in immune cell infiltration and apoptosis. Treatment with sildenafil led to a significant improvement in systolic and diastolic LV performance. This effect was associated with less LV hypertrophy, remodeling, cardiac inflammation and apoptosis. PDE5A inhibition with sildenafil may provide a new treatment strategy for cardiac hypertrophy and adverse remodeling in the hypertensive heart.

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Acknowledgments

We thank Kerstin Puhl, Georg Zingler, and Nadine Orrin for excellent technical assistance. This study was funded by the Deutsche Forschungsgesellschaft (SFB TR-19; A2, Z3).

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Correspondence to Dirk Westermann.

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D. Westermann and P. M. Becher contributed equally to this work.

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Westermann, D., Becher, P.M., Lindner, D. et al. Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo. Basic Res Cardiol 107, 308 (2012). https://doi.org/10.1007/s00395-012-0308-y

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