Spatio-specific CaMKII activation in cardiomyocytes from hypertensive Dahl salt-sensitive rats.

Hypertension, the number one risk factor for heart failure development, is one of the largest unmet medical needs in cardiovascular medicine. New evidence positions Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation as a driver of hypertension-induced cardiac remodeling. However, it remains to be elucidated what the precise effect of localisation-dependent activation is. Our most recent data show that the spatio-temporal CaMKII activation profile is crucial for determining whether it takes a protective or maladaptive role. Namely, its activation in the cytoplasm and on the nuclear envelope can speed up calcium uptake and release from cellular calcium stores on a beat-to-beat basis, while activation in the nucleoplasm triggers maladaptive gene signaling. We therefore performed subcellular immunocytochemistry analysis directed against phosphorylated CaMKII (pCaMKII) in isolated cardiomyocytes from hypertensive Dahl-salt sensitive rats at two disease stages. Additionally, we treated a subset of cells with the beta-adrenergic agonist isoprenaline to investigate the effect of short term stress induction. We observed lower pCaMKII levels in the nucleoplasm of early-stage hypertensive rats, while levels in the cytoplasm and at the nuclear envelope remained unchanged compared to age-matched control rats. Late-stage hypertension resulted in elevated pCaMKII levels in the cytoplasm, at the nuclear envelope and in the nucleoplasm. Upon short-term beta-adrenergic stimulation activation of CaMKII in the cytoplasm and at the nuclear envelope of both groups increased, while only hypertensive rats responded with elevated pCaMKII levels in the nucleoplasm. Taken together, our findings indicate that the spatio-specific CaMKII activation profile is altered in hypertension-induced cardiac remodeling and dependent on the disease stage. Further, hypertension escalates the response of CaMKII to beta-adrenergic stimulation in the nucleoplasm. These findings will provide new evidence to develop better therapeutic strategies fine-tuning spatio-specific CaMKII activation.