Cardiac Protease-Activated Receptor 2 expression is involved in cardiac fibrosis, diastolic dysfunction and immunological response in the aged heart

J. Friebel1, M. Witkowski1, A. Weithäuser1, K. Savvatis2, D. Steffens1, M. Kasner1, T. Tabaraie1, M. Wegner1, U. Landmesser1, U. Rauch-Kröhnert1 (1Berlin, Germany, 2London, United Kingdom)

Date: 16.02.2017,
Time: 11:00 - 12:00

Objective: Elderly patients often suffer from heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy and diastolic dysfunction. Until now, no treatment has been shown to reduce disease burden in these patients. The protease activated receptor (PAR) 2 is known to be a pro-fibrotic mediator. In a mouse model of myocardial infarction PAR-2 overexpression in cardiomyocytes led to the development of fibrosis. In this study we examine the role of PAR-2 in the aged heart regarding fibrosis, hemodynamic function and immunological response.

Methods: 8 weeks (wks) and 1 year (yr) old wild-type (wt) and PAR-2 knockout (ko) mice underwent hemodynamic measurements with a 1.2F microconductance catheter and hearts were collected for histological and biochemical analysis. Immune response and endothelial activation in wt and PAR-2ko hearts were analyzed with quantitative polymerase chain reaction and immunohistochemistry. The PAR-2 gene expression and PAR-2 related immunological status was determined in myocardial biopsies from patients with cardiac fibrosis.

Results: 1-year-old PAR-2ko mice showed a HFpEF-like phenotype. They suffered from a left ventricular dysfunction with preserved systolic function which was accompanied by an age dependent fibrosis and cardiac hypertrophy. Fibrosis associated TGF beta signaling was more enhanced in hearts of PAR-2ko mice. Whereas there was no difference in innate immune cell infiltration of macrophages and neutrophil granulocytes, PAR-2ko mice showed an increased T cell response as shown by an enhanced CD3+ cell infiltration and Interferon gamma expression. In HFpEF patients with cardiac fibrosis, a decreased PAR-2 expression was associated with severe diastolic dysfunction and vice versa.

Conclusion: The cardiac PAR-2 expression is associated with a HFpEF like phenotype in the aged heart. The loss of PAR-2 results in increased age-dependent cardiac fibrosis, a left ventricular diastolic dysfunction and increased T cell response.