Impact of systemic versus cardiomyocyte-specific alarmin S100A9 expression on heart failure

Kathleen Pappritz (Berlin)1, M. El-Shafeey (Berlin)1, I. M. Voss (Berlin)1, I. Matz (Berlin)1, M. Busch (Heidelberg)2, A. Jungmann (Heidelberg)2, N. Hamdani (Bochum)3, P. Most (Heidelberg)2, C. Tschöpe (Berlin)4, S. Van Linthout (Berlin)1

1Charité - Universitätsmedizin Berlin BIH Center für regenerative Therapien (BCRT) Berlin, Deutschland; 2Universitätsklinikum Heidelberg Innere Medizin III, Inst. für Molekulare und Translationale Kardiologie Heidelberg, Deutschland; 3Kath. Klinikum Bochum Cellular Physiology Bochum, Deutschland; 4Charité - Universitätsmedizin Berlin CC11: Med. Klinik m.S. Kardiologie Berlin, Deutschland


Background: It has been postulated that a systemic, low-grade inflammation induced by comorbidities underlies heart failure (HF) with preserved ejection fraction (HFpEF), whereas a local cardiac damage underlies HF with reduced ejection fraction (HFrEF). Accumulating evidence, including of our own, states the relevance of the alarmin S100A8/A9 in HFrEF and in comorbidities like diabetes mellitus and obesity, underlying HFpEF. However, the relevance of specific systemic or cardiomyocyte S100A9 expression on the pathogenesis of (different forms of) HF has not been investigated before.

Aim: The present study aimed to unravel the impact of systemic (hepatocyte-specific) versus cardiomyocyte-specific S100A9 expression on the pathogenesis of HF.

Methods: To achieve this goal, adeno-associated viral vectors (AAV) were generated: AAV5, directed to the liver with S100A9 or Luciferase driven by the hepatocyte-specific promoter Lp1 and 4 apo E enhancers and AAV9 directed to the heart, with S100A9 or luciferase driven by the cardiomyocyte-specific Trop T promoter. A dose of 3 × 1011 viral particles (vgc) of AAV5- and AAV9-S1009 vectors, and respective control vectors (AAV5-Luciferase and AAV9-Luciferase) or PBS was i.v. injected into 8-week-old male C57BL/6j mice. Cardiac function and deformation behavior were analyzed by conventional and STE-echocardiography. After 3 months, organs were harvested for molecular biological, immunohistochemical analyses, flow cytometry, and passive force measurements.

Results: AAV5-S100A9 gene transfer increased serum S100A8/A9 and C-reactive protein levels and was associated with alterations in strain parameters (reduced GLS and GRS), while the ejection fraction (EF) remained unchanged. In contrast, AAV9-S100A9 transfer led to an increased LV S100A9 mRNA and protein expression (positive heart area) without altering serum S100A8/A9 levels. This resulted in a decrease in EF, GLS, and GRS. Both AAV5- and AAV9-S100A9 vectors had no effect on cardiac fibrosis, but increased the passive force of cardiomyocytes. AAV5-S100A9 raised splenic CD68+NLRP+ and CD68+IL-1ß+ splenocytes, but did not increase LV CD68 and Ly6G+ cells. In contrast, CD68+NLRP+ and CD68+IL-1ß+ splenocytes were not upregulated after AAV9-S100A9 transfer, whereas LV Ly6G+ cells were increased after AAV9-S100A9 transfer.

Conclusion: Our data provide the first evidence that the origin of S100A9 overexpression (extra-cardiac or cardiac) influences the pathogenesis of HF.
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