CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect

Abstract

Key points: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca²⁺ /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise.

Abstract: The present study investigated whether oxidative stress and Ca²⁺ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKO^CaMKII ). In snap-frozen WT hearts, force-pCa relationship, H₂ O₂ generation, CaMKII oxidation and phosphorylation of myofilament and Ca²⁺ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H₂ O₂ generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKO^CaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca²⁺ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca²⁺ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca²⁺ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.

Keywords: Anrep effect; Ca2+ handling proteins; CaMKII; LV contractility; cMyBP-C; elastance-time curve; end-systolic elastance (Ees); myofilament phosphorylation.