Natriuretic Peptide Receptor-C Protects Against Angiotensin II-Mediated Sinoatrial Node Disease in Mice

Martin Mackasey; Emmanuel E Egom; Hailey J Jansen; Rui Hua; Motahareh Moghtadaei; Yingjie Liu; Jaspreet Kaur; Megan D McRae; Oleg Bogachev; Sara A Rafferty; Gibanananda Ray; Adam W Kirkby; Robert A Rose

doi:10.1016/j.jacbts.2018.08.004

Natriuretic Peptide Receptor-C Protects Against Angiotensin II-Mediated Sinoatrial Node Disease in Mice

JACC Basic Transl Sci. 2018 Dec 5;3(6):824-843. doi: 10.1016/j.jacbts.2018.08.004. eCollection 2018 Dec.

Authors

Martin Mackasey^{1

2}, Emmanuel E Egom², Hailey J Jansen^{1

2}, Rui Hua², Motahareh Moghtadaei², Yingjie Liu¹, Jaspreet Kaur¹, Megan D McRae¹, Oleg Bogachev², Sara A Rafferty², Gibanananda Ray², Adam W Kirkby¹, Robert A Rose^{1

2}

Affiliations

¹ Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada, and Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
² Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Abstract

Sinoatrial node (SAN) disease mechanisms are poorly understood, and therapeutic options are limited. Natriuretic peptide(s) (NP) are cardioprotective hormones whose effects can be mediated partly by the NP receptor C (NPR-C). We investigated the role of NPR-C in angiotensin II (Ang II)-mediated SAN disease in mice. Ang II caused SAN disease due to impaired electrical activity in SAN myocytes and increased SAN fibrosis. Strikingly, Ang II treatment in NPR-C^-/- mice worsened SAN disease, whereas co-treatment of wild-type mice with Ang II and a selective NPR-C agonist (cANF) prevented SAN dysfunction. NPR-C may represent a new target to protect against the development of Ang II-induced SAN disease.

Keywords: AP, action potential; Ang II, angiotensin II; CV, conduction velocity; DD, diastolic depolarization; Gmax, maximum conductance; HR, heart rate; ICa,L, L-type calcium current; ICa,T, T-type calcium current; INCX, sodium–calcium exchanger current; IV, current voltage relationship; If, hyperpolarization-activated current; NP, natriuretic peptide; NPR, natriuretic peptide receptor; NPR-C, natriuretic peptide receptor C; SAN, sinoatrial node; SBP, systolic blood pressure; V1/2(act), voltage for 50% channel activation; cSNRT, corrected sinoatrial node recovery time; fibrosis; hypertension; ion currents; natriuretic peptide; sinoatrial node.