Project 8: The impact of STAT1-dependent leukocyte responses in heart failure

PI Göttingen: T. Meyer; PI London: A. Ivetic; PhD: A. Doudin - finished PhD, Double degree

Scientific background and preliminary results

The pathogenesis of heart failure carries a strong inflammatory component, although the underlying molecular mechanisms of this complex aetiology are poorly understood. Cardiac hypertrophy and cardiogenic pulmonary edema are key pathophysiological responses to mechanical stretch and hemodynamic loads, and have long been considered to be predictive risk factors for adverse cardiovascular events. In patients with congestive heart failure, elevated levels of circulating cytokines have been identified, which may contribute to decreasing the functional status of these patients.

It is well known that extracellular cytokines such as interleukins (IL) and interferons (IFN) signal through distinct members of the protein family of signal transducers and activators of transcription (STATs). Upon binding of a cytokine to its cognate membrane receptor, STATs become phosphorylated on a signature tyrosine residue in their carboxy-terminus. Animal studies have shown that the common receptor subunit of the IL-6 glycoprotein 130 (gp130) is phosphorylated in response to pressure overload, which results in the subsequent activation of STAT1 and STAT3 (Hilfiker-Kleiner et al., 2010).

While the cardioprotective role of STAT3 in cardiac hypertrophy and myocardial infarction is well established both in transgenic mice and humans, much less is known about the function of its counterpart STAT1 in the development and course of pressure overload-induced cardiac hypertrophy and pulmonary hypertension. The presented project is aimed to dissect the functional role of STAT1 tyrosine (and serine) phosphorylation in cardiac hypertrophy and lung tissue remodelling induced by pressure overload. In particular, we will focus on the contribution of STAT1-mediated cytoskeletal reorganization in the onset and course of (i) adaptive hypertrophy of the myocardium and (ii) immune cell infiltration of the heart and lung by inflammatory cells following transverse aortic constriction (TAC).

Hypotheses of the PhD project

The cytokine IFNg plays a fundamental role in modulating leukocyte behavioral responses through a STAT1-dependent signalling pathway. Subverting leukocyte behaviour through STAT1 within the stressed heart and lung may act to minimize the extent of damage during heart failure. In the project the doctoral researcher will work on the following hypotheses:

1. We hypothesize that transgenic mice lacking STAT1 or expressing a tetramerization-deficient mutant of STAT1 will show more severe cardiac hypertrophy of the lung after pTAC surgery. The STAT1 knockout and -knockin mouse lines are assumed to exhibit enlarged left ventricles, increased cardiac-myocyte cell width and enhanced expression of hypertrophic genes, such as b-myosin heavy chain (b-MHC), as compared to wild-type mice. The degree of hypertrophy development and the time frame in which cardiac failure and hypertrophy develops will differ between the STAT1 genotypes.

2. Additionally, aortic constriction-induced heart failure may lead to increased lung weight in the transgenic mouse lines resulting from a significant increase in the percentage of fully muscularized lung vessels and a marked vascular and lung fibrosis.

3. In animals lacking functionally active STAT1, the IFNg-induced arrest in leukocyte migration should be at least partially impaired resulting in enhanced leukocyte infiltration of the heart and lung.

Contact