Stimulation of Erythrocyte Soluble Guanylyl Cyclase Induces cGMP Export and Cardioprotection in Type 2 Diabetes

Tong Jiao; Aida Collado; Ali Mahdi; John Tengbom; Yahor Tratsiakovich; G Todd Milne; Michael Alvarsson; Jon O Lundberg; Zhichao Zhou; Jiangning Yang; John Pernow

doi:10.1016/j.jacbts.2023.02.017

Stimulation of Erythrocyte Soluble Guanylyl Cyclase Induces cGMP Export and Cardioprotection in Type 2 Diabetes

JACC Basic Transl Sci. 2023 Aug 21;8(8):907-918. doi: 10.1016/j.jacbts.2023.02.017. eCollection 2023 Aug.

Authors

Tong Jiao^{1

2}, Aida Collado¹, Ali Mahdi¹, John Tengbom¹, Yahor Tratsiakovich¹, G Todd Milne³, Michael Alvarsson⁴, Jon O Lundberg⁵, Zhichao Zhou¹, Jiangning Yang¹, John Pernow^{1

6}

Affiliations

¹ Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
² Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Cyclerion, Cambridge, Massachusetts, USA.
⁴ Division of Endocrinology and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Cardiology, Heart and Vascular Division, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Reduced nitric oxide (NO) bioactivity in red blood cells (RBCs) is critical for augmented myocardial ischemia-reperfusion injury in type 2 diabetes. This study identified the nature of "NO bioactivity" by stimulating the intracellular NO receptor soluble guanylyl cyclase (sGC) in RBCs. sGC stimulation in RBCs from patients with type 2 diabetes increased export of cyclic guanosine monophosphate from RBCs and activated cardiac protein kinase G, thereby attenuating ischemia-reperfusion injury. These results provide novel insight into RBC signaling by identifying cyclic guanosine monophosphate from RBC as a mediator of protection against cardiac ischemia-reperfusion injury induced by sGC stimulation in RBCs.

Keywords: cyclic guanosine monophosphate; infarct size; ischemia-reperfusion; nitric oxide; protein kinase G; red blood cell.