Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo.

Abstract

Inhibition of the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) or depletion of sarcoplasmic reticulum (SR) Ca(2+) stores protects against apoptosis from excessive isoproterenol (Iso) stimulation in cultured ventricular myocytes, suggesting that CaMKII inhibition could be a novel approach to reducing cell death in conditions of increased adrenergic tone, such as myocardial infarction (MI), in vivo. We used mice with genetic myocardial CaMKII inhibition due to transgenic expression of a highly specific CaMKII inhibitory peptide (AC3-I) to test whether CaMKII was important for apoptosis in vivo. A second line of mice expressed a scrambled, inactive form of AC3-I (AC3-C). AC3-C and wild-type (WT) littermates were used as controls. AC3-I mice have reduced SR Ca(2+) content and are resistant to Iso- and MI-induced apoptosis compared with AC3-C and WT mice. Phospholamban (PLN) is a target for modulation of SR Ca(2+) content by CaMKII. PLN(-/-) mice have increased susceptibility to Iso-induced apoptosis. Verapamil pretreatment prevented Iso-induced apoptosis in PLN(-/-) mice, indicating the involvement of a Ca(2+)-dependent pathway. AC3-I and AC3-C mice were bred into a PLN(-/-) background. Loss of PLN increased and equalized SR Ca(2+) content in AC3-I, AC3-C, and WT mice and abolished the resistance to apoptosis in AC3-I mice after MI. There was a trend (P = 0.07) for increased Iso-induced apoptosis in AC3-I mice lacking PLN compared with AC3-I mice with PLN. These findings indicate CaMKII is proapoptotic in vivo and suggest that regulation of SR Ca(2+) content by PLN contributes to the antiapoptotic mechanism of CaMKII inhibition.

• Authors: Yingbo Yang, Wei-Zhong Zhu, Mei-ling Joiner, Rong Zhang, Carmine V Oddis, Yue Hou, Jinying Yang, Edward E Price, Linda Gleaves, Mesut Eren, Gemin Ni, Douglas E Vaughan, Rui-Ping Xiao, Mark E Anderson
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 291 Issue 6 Pg. H3065-75 (Dec 2006) ISSN: 0363-6135 [Print] United States
• PMID: 16861697 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adrenergic beta-Agonists
• Calcium Channel Blockers
• Calcium-Binding Proteins
• Camk2n2 protein, mouse
• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• phospholamban
• Verapamil
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium-Calmodulin-Dependent Protein Kinases
• Isoproterenol
• Calcium

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Apoptosis (drug effects, physiology)
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Calcium-Binding Proteins (genetics, metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium-Calmodulin-Dependent Protein Kinases (antagonists & inhibitors, physiology)
• Carrier Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation
• Intracellular Signaling Peptides and Proteins
• Isoproterenol (pharmacology)
• Male
• Mice
• Mice, Transgenic
• Myocardial Infarction (metabolism, pathology, physiopathology)
• Myocardium (metabolism, pathology)
• Sarcoplasmic Reticulum (metabolism)
• Signal Transduction (physiology)
• Verapamil (pharmacology)