Abstract
Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms governing the progression to heart failure are incompletely understood. Recent studies on altered translational regulation during pathological cardiac hypertrophy are contributing to our understanding of disease progression. In this brief review, we describe how the translational machinery is modulated for enhanced global and transcript selective protein synthesis, and how alternative modes of translation contribute to the disease state. Attempts at controlling translational output through targeting of mTOR and its regulatory components are detailed, as well as recently emerging targets for pre-clinical investigation.
Highlights
IntroductionThe majority of cardiomyocytes lose their ability to proliferate shortly after birth
Upon terminal differentiation, the majority of cardiomyocytes lose their ability to proliferate shortly after birth
While a great deal is known about the underlying stimuli and pathological remodeling associated with cardiac hypertrophy, new details are still emerging regarding the molecular mechanisms governing regulation of protein translation necessary for cellular hypertrophic growth, and their role in the progression to heart failure
Summary
The majority of cardiomyocytes lose their ability to proliferate shortly after birth. While a great deal is known about the underlying stimuli and pathological remodeling associated with cardiac hypertrophy, new details are still emerging regarding the molecular mechanisms governing regulation of protein translation necessary for cellular hypertrophic growth, and their role in the progression to heart failure. Translational regulation is increasingly recognized as a means for tissue to rapidly respond to environmental stress This has direct implications for identifying molecular markers of disease where mRNA abundance has historically served as a proxy for protein expression. Canonical eukaryotic translation initiation employs a ribosome scanning mechanism to identify an AUG start codon [8]. This cap-dependent mechanism of translation initiation comprises several well defined steps (reviewed in [9]). Components of translational regulation whose functions are involved in pathological stress in cardiac hypertrophy and progression to heart failure are discussed below
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