Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Surprisingly, Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50% reduction of T-box transcription factors cause disease. Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome conduction system defects, suggest mechanisms for intrafamilial phenotypic variability, and account for related cardiac malformations caused by other transcription factor mutations.
In recent years, significant progress has been made in understanding cardiomyocyte differentiation. However, little is known about the regulation of myocyte survival despite the fact that myocyte apoptosis is a leading cause of heart failure. Here we report that transcription factor GATA-4 is a survival factor for differentiated, postnatal cardiomyocytes and an upstream activator of the antiapoptotic gene Bcl-X. An early event in the cardiotoxic effect of the antitumor drug doxorubicin is GATA-4 depletion, which in turn causes cardiomyocyte apoptosis. Mouse heterozygotes for a null Gata4 allele have enhanced susceptibility to doxorubicin cardiotoxicity. Genetic or pharmacologic enhancement of GATA-4 prevents cardiomyocyte apoptosis and drug-induced cardiotoxicity. The results indicate that GATA-4 is an antiapoptotic factor required for the adaptive stress response of the adult heart. Modulation of survival͞apoptosis genes by tissue-specific transcription factors may be a general paradigm that can be exploited effectively for cell-specific regulation of apoptosis in disease states.transcription ͉ apoptosis ͉ Bcl-X ͉ doxorubicin ͉ ␣1-adrenergic receptors
Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of AII at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse ␣-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases.T he growth response of the adult heart to mechanical overload is enlargement of terminally differentiated cardiomyocytes resulting in heart hypertrophy. This phenotypic change is associated with reprogramming of cardiac gene expression, including reinduction of a set of fetal genes for which atrial natriuretic factor (ANF) is a hallmark (1, 2). Cardiac hypertrophy is often accompanied by cardiac remodeling characterized by cardiomyocyte loss, proliferation of interstitial fibroblasts, and collagen deposition, leading to decreased compliance and increased risk for heart failure (3-6). Although the exact mechanisms involved in initiating and͞or maintaining cardiac hypertrophy remain unknown, many neurohumoral systems, particularly the reninangiotensin system (RAS), have been implicated in the hypertrophic process (reviewed in ref. 7).RAS is a major determinant of arterial pressure and volume homeostasis in mammals through the action of the vasoactive peptide angiotensin II (AII) on vascular AII type 1 receptor (AT1R) (8). The activity of RAS is increased in several cardiovascular diseases, such as myocardial infarction, myocarditis, cardiomyopathy, and hypertension. It is now well established that angiotensin converting enzyme inhibitors prevent the development of pressure-overload cardiac hypertrophy in animal models and in hypertensive human patients; more recently, AT1R antagonists were found to be effective at repressing cardiac hypertrophy in hype...
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