Scientifically, this research program views the enlargement of the left ventricular cardiac muscle (cardiac hypertrophy or left ventricular hypertrophy, LVH) as the main biologically pathogenic process in heart failure. A hallmark feature of pathological LVH is re-activation of a fetal gene expression profile, a feature that is lacking in exercise-induced cardiac enlargement. Accordingly, we view maladaptive LVH as a phenomenon that entails not only quantitative changes (increase in individual cell mass) but also qualitative alterations (induction of fetal over adult genes), that inevitably instigates dedifferentiation of adult heart muscle cells and hemodynamic dysfunction at the complete organ level.
A large number of cytoplasmic, parallel signaling mechanisms has been uncovered to transmit heart failure signals, and convert these stimuli to the cellular level by activation of a limited set of transcription factors. Studies in our program have demonstrated that the pro-hypertrophic properties of the serine-threonine protein phosphatase calcineurin are contingent upon activation of its immediate downstream transcription factor Nuclear Factor of Activated T-cells (NFAT), leading us to believe that activation of the transcription factor NFAT represents one nodal point in the control of re-activation of fetal gene expression, cardiac hypertrophy and heart failure. Part of our research program is to identify and characterize the function of new regulators of NFAT transcription factors and to discover new transcription factors that evoke a so called “fetal gene program” in the setting of heart failure stimuli, in an effort to provide a more fundamental perspective of the pathogenesis of heart failure.
MicroRNAs (miRNAs) and other species of non-coding RNAs (ncRNAs) regulate the translation of target messenger RNAs, providing an exciting novel dimension for control of critical regulators in heart failure. MicroRNAs are small, noncoding RNAs (20-23 nucleotides) that negatively regulate gene expression at the post-transcriptional level by base-pairing with complementary sequences in the 3’ untranslated regions (UTRs) of protein-coding transcripts. There are estimates that over 1000 microRNAs are encoded in the human genome. Individual mRNAs are commonly targeted by multiple microRNAs, while one single microRNA can regulate multiple species of messenger RNAs, allowing for enormous regulatory potential, reminiscent of transcription factors that coordinately regulate multiple genes. The discovery of cholesterolmodified and chemically stabilized short RNA-molecules (termed “antagomirs“) that allow the sustained knockdown of endogenous single microRNAs in the adult mouse heart in vivo following single intravenous injection, opens the potential for therapeutic testing in large animal models and fast firstto-man approaches. In the second part of our research program, we will provide an inventory of relevant heart failure microRNAs using deep sequencing approaches of human heart failure libraries, and we will perform specific and genetic interventions at the level of a select number of single microRNAs to uncover their model of action in heart failure.
Besides chronic hypertension, viral infections and diabetes, where cellular loss is limited, myocardial infarction is a major cause of heart failure and cardiac death. Mature cardiomyocytes do not divide and those lost in an infracted ventricle are gradually replaced by fibroblasts to form scar tissue, provoking a dramatic loss of contractile force. The scarcity of cardiogenic conversion by endogenous hematopoietic cells, uncertain proof for myocytes of host origin in transplanted human hearts, the confounding possibility of cell fusion after grafting in vivo, and obvious ethical obstacles surrounding material from embryonic origins, all highlight unsettled issues surrounding stem cell plasticity in heart disease. These obstacles underscore the need to identify, characterize and manipulate resident cardiac progenitor cells in situ. However, essential characteristics of this cardiac precursor cell pool, such as signaling mechanisms maintaining ES cell pluripotency and signals directing ES cell cardiogenic differentiation, are largely unknown. A final part of our research program is to use our expertise on transcription factors and microRNAs to understand the fundamentals behind ES cell behavior with the ultimate goal to achieve manipulation of resident progenitor cells in the murine heart and/or more efficient manageability of iPS directed cardiogenesis for purposes of cardiac repair.