Ca ²⁺ /calmodulin‐dependent protein kinase II and protein kinase G independently contribute to acutely enhance myocardial compliance with stretch

The heart constantly adapts to acute hemodynamic load by increasing contractility and stretch-induced compliance (SIC). The latter involves titin phosphorylation, notably by cGMP-dependent protein kinase (PKG). Given that Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) also phosphorylates titin and is activated under acute stress via redox signaling, we hypothesized a role for CaMKII in SIC. We assessed passive tension (PT) decay in the 15 min following sudden stretch in isometrically contracting rabbit right ventricular papillary muscles, with or without PKG or CaMKII inhibition. Additionally, Wistar Han rat hearts were Langendorff-perfused and acutely stretched or left unstretched. Skinned cardiomyocytes extracted from these hearts were analyzed for sarcomere length-PT relationships before and after incubation with PKG, CaMKII, or both. Both kinases reduced PT, with diminished effects in pre-stretched cells, suggesting prior kinase activation. PKG inhibition significantly blunted SIC, while CaMKII inhibition showed a similar but non-significant trend. Our findings support that CaMKII contributes to SIC, likely via shared phosphorylation targets with PKG. These results provide mechanistic insight into SIC and suggest CaMKII as a potential modulator of diastolic function during acute stretch, such as in preload challenges.