Research

We investigate the mechanisms for initiation/regression of cardiac hypertrophy (CH) with heart failure (HF). We contend that this condition is initiated in myocardium by mechanical/humoral signals that produce a factor – myotrophin (myo) – that triggers myocyte protein synthesis. Myo interacts with nuclear factor-κB (NFκB) and p53 in what may be a common pathway for future targeted drug intervention to prevent/mitigate CH. We use transgenic (Tg) mouse models, small-interfering RNA techniques for gene silencing, and tetracycline transactivation in the myo gene, as well as pharmacological treatments, to define the mechanism of action of myo at cellular, morphological and molecular levels and correlate our findings with functional echocardiographic studies.

Since first identifying myo from hearts of spontaneously hypertensive rats and humans with CH, we have studied why myo levels surge in hypertrophy. Overexpression of myo in Tg mice results in CH progressing to HF. This mouse model, which mimics human CH/HF, provides a new tool for studying molecular changes during CH progression to HF. We now have another “tet” Tg mouse line. We know that myo is involved in activating the NFκB pathway, cell division/apoptosis occurs at the point of failure, and p53 is also overexpressed. We are now turning the myo gene on/off to explore the role of p53 and to elucidate how myo affects cardiac mass, gene expression, NFκB, growth factors, cytokines, and protein levels.  We aim eventually to understand how myo protein synthesis can selectively be turned on/off by certain agents. We will then hold a crucial key to therapeutic planning for patients with hypertensive CH/HF.