OP2 Knock-out of MG23 cardioprotects against pressure-overload induced cardiac hypertrophy and cardiac dysfunction

In the failing heart, Ca²⁺-cycling is profoundly altered, leading to leak of Ca²⁺ from the sarcoplasmic reticulum (SR)¹. This results in impaired cardiac contraction and arrhythmias. The underlying molecular mechanisms governing SR Ca²⁺ leak are unclear. Mitsugumin 23 (MG23) is a Ca²⁺-conducting ion channel located on ER/SR and nuclear membranes². The Pitt laboratory have shown MG23-mediated Ca²⁺-release increases under pathophysiological conditions³. This suggests MG23 plays a role in diastolic SR Ca²⁺ leak and may be involved in heart failure progression. The aim of this research is to investigate the role of MG23 in SR Ca²⁺ leak and progression of heart failure. Pressure-overload was induced in MG23-knock out (KO) and wild type (WT) mice using Angiotensin II (AngII, 1.1 mg/kg/day) delivered subcutaneously by an osmotic mini pump (Alzet). Dynamic cardiac functions were measured in vivo using pressure-volume loop (Transconic). Ventricular fibrosis and cardiomyocyte size were also measured using histological (Picrosirius Red staining) and immunofluorescence (WGA) approaches. Work was carried out under project licences of S.J. Pitt and C.E. Murdoch in compliance with UK Home Office – Operation of the Animals (Scientific Procedures) Act, 1986. In the pressure-overload induced heart failure mouse model, we show that MG23-KO provided cardiovascular protection against the adverse effects of AngII. MG23-KO attenuated AngII-induced cardiac hypertrophy, altered cardiac function and hypertension. We also show a marked reduction in AngII-induced fibrosis in MG23-KO animals compared to WT controls. This data suggests that MG23 plays a key role in driving Ca²⁺ dysregulation observed in the early pathological stages of pressure-overload induced heart failure. This work was funded by the British Heart Foundation.