The role of CaMKII in the structural and functional remodelling of cardiac myocytes in heart failure with preserved ejection fraction

Calcium (Ca2+) signalling is an essential pathway that regulates the function of cardiac myocytes (CMs) and the heart as a whole. This process is remodelled in Heart Failure with preserved Ejection Fraction (HFpEF), a condition of diastolic dysfunction that is associated with diabetes, hypertension and obesity, amongst others. Our in vivo heart failure models have revealed that Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates the remodelling of Ca2+ signalling in the whole heart. Additionally, our in vitro HFpEF model demonstrates alterations in global and localised Ca2+ release, under hyperglycaemic and hypertensive conditions.

Here we investigated the cellular structural and functional modifications induced by hyperglycaemia and hypertension, relative to the presence of a CaMKII inhibitor (KN93). Primary CMs were isolated from adult New Zealand White rabbits through Langendorff perfusion. These cells were cultured for 24 hours in Medium 199 containing either glucose (22mM) to simulate hyperglycaemia in diabetes and/or Angiotensin II (200nM) to simulate hypertension. In parallel, CMs were pre-treated with KN93 (5µM) before diabetic and hypertensive conditioning. To investigate functional alterations, CMs were loaded with a calcium indicator and electrically field-stimulated. In addition, Wheat Germ Agglutinin stain was utilised to identify transverse (T)-tubule structures, which were observed by confocal microscopy.

Preliminary data suggests a dyssynchrony of Ca2+ transient release in CMs during
hyperglycaemia. Moreover, T-tubule density was depleted coupled with an increased half distance between T-tubule structures, following hyperglycaemic conditioning. Furthermore, current findings indicate that differential mechanisms influence the remodelling of Ca2+ signalling under hyperglycaemic and hypertensive conditions. The inhibition of these cellular modifications by the presence of KN-93, allude to the influence of CaMKII in these pathological conditions. Ongoing work is investigating the relationship between the cardiac cellular remodelling induced by these individual effectors, in vitro, to cardiac alterations observed in our in vivo HFpEF model.