Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy.
Beneficial cardiac effects of growth hormone (GH) have been shown in heart failure in several settings, but studies are lacking on this and other forms of treatment in the cardiomyopathic (CM) mouse heart. In mice with dilated cardiomyopathy due to disruption of the muscle LIM protein (MLP) gene [MLP null mice (MLP-/-)], natural history was first assessed by an initial echocardiogram at 8 weeks and a later follow-up study (n = 31). In most mice, left ventricular (LV) dilation increased and/or function decreased by 5 months, and 3 of 12 mice followed for 9 months died. At the end of follow-up, 22 MLP-/- mice (average age 10.2 months) had both LV dilation and reduced LV function and were selected for studies of GH effects on cardiac function and gene expression; mice were randomized to vehicle (controls) or recombinant human (rh) GH and restudied after 2 weeks. In the GH-treated group compared to the control group, LV % fractional shortening and LV wall thickness (echocardiography) were increased, the LV dP/dtmax (catheter-tip micromanometry) was enhanced, and LV relaxation (tau) improved; however, the LV weight was not significantly increased. The LV expression of many genes was altered in MLP-/- mice, and several were influenced by GH. Thus, short-term RhGH treatment improved LV function in a setting of chronic cardiac deterioration and significantly reduced elevated LV mRNA expression of some (ANP, BNP) but not other members of the embryonic gene program. The MLP null cardiomyopathic mouse can be useful for exploring altered signaling and therapeutic interventions in heart failure.
Hongo
M
M
The First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Ryoke
T
T
Schoenfeld
J
J
Hunter
J
J
Dalton
N
N
Clark
R
R
Lowe
D
D
Chien
K
K
Ross
J
J
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D004452:Echocardiography; D015870:Gene Expression / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D016277:Ventricular Function, Left / Q000235:genetics
D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3; D013006:Growth Hormone