Adult Cardiac Expression of the Activating Transcription Factor 3, ATF3, Promotes Ventricular Hypertrophy

Abstract

Cardiac hypertrophy is an adaptive response to various mechanophysical and pathophysiological stresses. However, when chronic stress is sustained, the beneficial response turns into a maladaptive process that eventually leads to heart failure. Although major advances in the treatment of patients have reduced mortality, there is a dire need for novel treatments for cardiac hypertrophy. Accordingly, considerable efforts are being directed towards developing mice models and understanding the processes that lead to cardiac hypertrophy. A case in point is ATF3, an immediate early transcription factor whose expression is induced in various cardiac stress models but has been reported to have conflicting functional significance in hypertrophy. To address this issue, we generated a transgenic mouse line with tetracycline-regulated ATF3 cardiac expression. These mice allowed us to study the consequence of ATF3 expression in the embryo or during the adult period, thus distinguishing the effect of ATF3 on development versus pathogenesis of cardiac dysfunction. Importantly, ATF3 expression in adult mice resulted in rapid ventricles hypertrophy, heart dysfunction, and fibrosis. When combined with a phenylephrine-infusion pressure overload model, the ATF3 expressing mice displayed a severe outcome and heart dysfunction. In a complementary approach, ATF3 KO mice displayed a lower level of heart hypertrophy in the same pressure overload model. In summary, ectopic expression of ATF3 is sufficient to promote cardiac hypertrophy and exacerbates the deleterious effect of chronic pressure overload; conversely, ATF3 deletion protects the heart. Therefore, ATF3 may serve as an important drug target to reduce the detrimental consequences of heart hypertrophy.

ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling

“…Interestingly, cardiac-specific expression of both JDP2 and ATF3 during embryonic period results in atrial enlargement and premature death in transgenic mice [25][26][27]. In contrast, adult ATF3 expression is sufficient to induce ventricular hypertrophy even in the absence of additional insults such as pressure overload [27]. In line with these studies, ATF3 was found to be required for cardiomyocytes growth response to endothelin-1 stimulation [28].…”

“…All mice genotypes were backcrossed to C57Bl/6 background for at least 8 generations. Mice used in this study: ATF3-KO [33], ATF3-KO Flox [34] and αMHC-CRE mice [35], ATF3-Tg and αMHC-tTA [27]. Male mice were used in all the experiments performed in this study unless otherwise specified.…”

“…Importantly, ATF3 expression is highly induced specifically in cardiomyocytes following acute challenge with isoproterenol, PE and angiotensin II [24]. Interestingly, cardiac-specific expression of both JDP2 and ATF3 during embryonic period results in atrial enlargement and premature death in transgenic mice [25][26][27]. In contrast, adult ATF3 expression is sufficient to induce ventricular hypertrophy even in the absence of additional insults such as pressure overload [27].…”

Induction of activating transcription factor 3 limits survival following infarct-induced heart failure in mice

“…ATF3 can act as either a transcriptional activator or repressor, and is involved in the rapid regulation of many genes (26). Under normal conditions, ATF3 is not detectable in the heart, but is induced rapidly following myocardial ischemia (4,28).…”

“…Indeed, cardiac ATF3 overexpression may be sufficient to provoke conduction abnormalities and contractile dysfunction (28). Furthermore, ATF3 overexpression in otherwise healthy adult mice produces cardiac fibrosis, cardiac hypertrophy, and cardiac dysfunction (26); adult ATF3 overexpressing mice are also more susceptible to pressure overload-induced cardiac dysfunction, and complementary loss of function studies demonstrated that ATF3 deficiency reduces cardiomyocyte hypertrophy and protects the heart against pressure overload (26). Conversely, others have shown that ATF3 deficiency enhances cardiomyocyte hypertrophy in vitro, and ATF3 deficiency exacerbates cardiac fibrosis in a pressure overload model (40).…”