Protein phosphatase modulator CIP2A and non-canonical Wnt11 in cardiac remodeling and development of heart failure

Cardiovascular diseases are the leading cause of death in the Western adult population. The major cardiovascular pathologies and the use of cardiotoxic medications results in cardiac injury and predispose to heart failure. Despite modern medicine, the prognosis is poor for patients suffering from heart failure with a 5-year mortality rate of 50%. At the moment, there is no treatment that could stop or sufficiently reverse the progression of heart failure. In this thesis, two potential genes connected to cardiac remodeling and heart failure were studied: Wnt11 and Cip2a.

The non-canonical Wnt11 signaling protein is essential in the embryonic development of the heart, but its function after birth and in heart disease is largely unknown. In this thesis, the proliferation of cardiac muscle cells in newborn and juvenile mice was investigated and Wnt11 deficiency was found to slightly increase cell growth. The role of Wnt11 gene in heart disease was studied in adult mice subjected to a pressure overload in the heart. Wnt11 deficiency was found not to affect heart remodeling, myocardial thickening (pathological hypertrophy) or fibrosis. However, based on experiments with cardiac muscle cells, co-operation of non-canonical Wnt proteins may be required for an anti-hypertrophic effect in the stressed heart.

Protein phosphatase modulator CIP2A is a well-studied candidate for anti-cancer therapy, however its effects on the heart are unknown. Cardiac muscle cells with reduced Cip2a gene expression were investigated and the CIP2A deficiency weakened the stress response of the cardiomyocytes. In Cip2a-silenced mice, cardiac pressure overload showed that CIP2A deficiency reduced the pathological hypertrophy and remodeling of the myocardium. In addition, CIP2A deficiency protected the heart from impaired systolic function and the development of heart failure.

Altogether, these results demonstrated that the Wnt11 signaling alone is not sufficient to influence cardiac remodeling under stress, but together with Wnt5a, it may regulate the cardiac muscle cell growth. The CIP2A deficiency reduced pathological remodeling in the stressed heart without showing any cardiotoxic effects. Based on these findings, CIP2A is also a potential drug target for the treatment of heart diseases, such as heart failure.