A Genetic Mouse Model of Cardiac Hypertrophy and Failure
Over a decade ago we examined the hypothesis that the heart reacts to stress or injury as an endocrine response organ. Specifically, we tested the hypothesis that increased systemic release of the neurohormones angiotensin II, epinephrine, and endothelin were the stimulus for cardiac hypertrophy.
To avoid confounding effects of these hormones and their receptors (which potently increase blood pressure), we used genetic techniques to autonomously activate their signaling pathways by overexpressing their common signal transducer, Gaq.
The Gq mouse develops spontaneous cardiac hypertrophy, and can be further induced to progress to heart failure via cardiac myocyte apoptosis. The Gq mouse is widely used for genetic “rescues” of heart failure, and for research into transcriptional events associated with reactive cardiac hypertrophy.
Gq mouse hearts exhibit contractile dysfunction and pathological gene expression. A. Cross sections of nontransgenic (ntg) and Gq transgenic mouse hearts. B. M-mode echocardiography showing normal size and contraction of ntg hearts, with increased left ventricular dimension and reduced contraction of Gq heart. C. Invasive hemodynamic (“heart cath”) study showing normal contraction response to increasing doses of the ß1 adrenergic receptor agonist, dobutamine, but flat dobutamine response for Gq hearts. D. Real-time qPCR showing increased expression of atrial natriuretic factor (Nppa), skeletal actin (Acta1), and b-myosin heavy chain (Myh7) RNA, and decreased SERCA2a (Atp2a2) RNA, in Gq hearts, recapitulating the hallmark “fetal gene program” of pathological cardiac hypertrophy.
RNA sequencing of Gq hearts shows a pattern of altered gene expression, including apoptosis genes. Gene-ontology analysis of regulated genes in Gq transgenic hearts.
Identification of Nix/BNip3L as a regulated cell death gene in Gq hearts. Left panel, microarray analysis comparing Gq and nontransgenic gene expression. Circle indicates Nix/BNip3L. Right panel, northern blot analysis showing increased expression of multiple Nix/BNip3L transcripts in Gq and pressure overloaded (POH) mouse hearts and in human hypertensive heart (LVH).
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