A transgenic mouse model of heart failure using inducible Galpha q.
Receptors coupled to Galpha q play a key role in the development of heart failure. Studies using genetically modified mice suggest that Galpha q mediates a hypertrophic response in cardiac myocytes. Galpha q signaling in these models is modified during early growth and development, whereas most heart failure in humans occurs after cardiac damage sustained during adulthood. To determine the phenotype of animals that express increased Galpha q signaling only as adults, we generated transgenic mice that express a silent Galpha q protein (Galpha qQ209L-hbER) in cardiac myocytes that can be activated by tamoxifen. Following drug treatment to activate Galpha q Q209L-hbER, these mice rapidly develop a dilated cardiomyopathy and heart failure. This phenotype does not appear to involve myocyte hypertrophy but is associated with dephosphorylation of phospholamban (PLB), decreased sarcoplasmic reticulum Ca2+-ATPase activity, and a decrease in L-type Ca2+ current density. Changes in Ca2+ handling and decreased cardiac contractility are apparent 1 week after Galpha qQ209L-hbER activation. In contrast, transgenic mice that express an inducible Galpha q mutant that cannot activate phospholipase Cbeta (PLCbeta) do not develop heart failure or changes in PLB phosphorylation, but do show decreased L-type Ca2+ current density. These results demonstrate that activation of Galpha q in cardiac myocytes of adult mice causes a dilated cardiomyopathy that requires the activation of PLCbeta. However, increased PLCbeta signaling is not required for all of the Galpha q-induced cardiac abnormalities.
Fan
Gaofeng
G
Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA.
Jiang
Ya-Ping
YP
Lu
Zhongju
Z
Martin
Dwight W
DW
Kelly
Damon J
DJ
Zuckerman
Joan M
JM
Ballou
Lisa M
LM
Cohen
Ira S
IS
Lin
Richard Z
RZ
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D004487:Edema / Q000473:pathology; D004594:Electrophysiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000502:physiology*; D006331:Heart Diseases / Q000235:genetics*; D006439:Hemodynamics; D006801:Humans; D006984:Hypertrophy; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D054799:Phospholipase C beta; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism*
D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D004247:DNA; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000252:Calcium-Transporting ATPases; D002118:Calcium