Hypertrophic phenotype of cardiac calcium/calmodulin-dependent protein kinase II is reversed by angiotensin converting enzyme inhibition.
Calcium-dependent mechanisms and the renin angiotensin system (RAS) are critically involved in the hypertrophic growth of the myocardium. The calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator in calcium signaling and modulates calcium handling and growth mechanisms in cardiomyocytes. Here we present data on expression of cardiac isoforms of CaMKIIdelta, the dominant form in the myocardium, in compensatory hypertrophy of stroke-prone spontaneously hypertensive rats (SHRSP) compared to the normotensive Wistar-Kyoto (WKY) control strain. Cardiac hypertrophy in SHRSP was documented by an increased heart weight/body weight ratio (HW/BW) of 31% (p < 0.05) and a more than six-fold elevated atrial natriuretic factor (ANF) transcript level (p < 0.05). Compensatory hypertrophic growth in SHRSP produced a specific phenotype of CaMKIIdelta isoforms characterized by increased transcript levels of the embryonic/neonatal isoform delta4 (48%, p < 0.05) and the isoform delta9 (31%, p < 0.05) with no changes in delta2 and delta3. Inhibition of angiotensin converting enzyme (ACE) by cilazapril completely regressed myocardial hypertrophy, normalized ANF transcript levels, and restored the normal phenotype of CaMKIIdelta by reducing transcripts for delta4 and delta9 to levels present in WKY controls. Our data suggest the importance of specific changes in the CaMKII isoform composition for growth processes in the myocardium.
Hempel
P
P
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Hoch
B
B
Bartel
S
S
Karczewski
P
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017315:Cilazapril / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000235:genetics; D014158:Transcription, Genetic
D000806:Angiotensin-Converting Enzyme Inhibitors; D007527:Isoenzymes; D017315:Cilazapril; D009320:Atrial Natriuretic Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases