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Calcium‐calmoduline kinase II plays a important role in cardiac hypertrophy in ANP receptor deficient mice

Atrial natriuretic peptide (ANP), through its guanylyl cyclase‐A (GC‐A) receptor, not only is critically involved in endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. Our recent study demonstrated that ANP/GC‐A system counter‐regulates cardiac growth response to pressure overload by preventing activation of the myocardial Na+/H+ exchanger and subsequent increases in cardiomyocyte intracellular pHi and Ca2+i (Circulation 2005; 112:). In the present study we investigated the role of Ca2+‐calmodulin‐dependent kinase II (CaMKII) in altered Ca2+ handling and cardiac hypertrophy of GC‐A – deficient (GC‐A −/ −) mice. Both expression and autophosphorylation of CaMKII were increased in GC‐A ‐/− hearts. Fluorimetric measurements demonstrated increased Ca2+i transients in isolated GC‐A −/ − cardiomyocytes as compared to wildtypes. Inhibition of CaMKII with KN‐93 (10 μM, 5 min) attenuated Ca2+i transients in GC‐A −/ − cardiomyocytes and had no effect on WT cells. The inactive analog KN‐92 had no effect. Chronic treatment of GC‐A −/ − mice with KN‐93 (1 μmol/kg/d, i.p.,5 weeks) did not affect hypertensive phenotype but significantly reversed hypertrophy and fibrosis. These findings suggest that CaMKII has a critical role in altered cardiomyocyte Ca2+i handling and cardiac remodelling of GC‐A −/ − mice.