https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Gießen und Marburg GmbH Klinik für Herz-, Kinderherz- und Gefäßchirurgie Gießen, Deutschland; 2Physiologie, Justus-Liebig-Universität Gießen Gießen, Deutschland; 3Rudolf Buchheim Institute für Pharmakologie, Justus-Liebig-Universität Giessen Gießen, Deutschland; 4Justus-Liebig-Universität Giessen Physiologisches Institut Gießen, Deutschland
Background
The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV), which limits direct application of the substantial knowledge concerning LV failure for improving RV function. To identify molecular signatures and mechanisms of heart failure (HF) specific to the RV, we established animal models, which show two clearly distinguishable, slowly developing stages of disease (compensated and decompensated) in response to aortic or pulmonary artery banding (AOB, PAB) in rats. By RNA-seq. we identified a number of genes that are specifically deregulated in the RV upon PAB, in particular a cluster of dual-specificity phosphatases (DUSPs). These DUSPs or MAPK phosphatases control the spatiotemporal inactivation of MAPKs and are thus involved in the control of cardiac growth and remodeling.
Methods and Results
PAB and AOB were performed in weanling rats to reach a stage of compensatory hypertrophy 7 weeks after surgery or RV/LV failure (RVF/LVF) 22 or 26 weeks after surgery respectively. Cardiac function was characterized by high-resolution echocardiography, micro-CT and pressure-volume loops. To verify the changes in DUSP expression observed by RNA-seq., RT-qPCR and Western blots were performed.
At both disease stages, a number of DUSPs were differentially regulated compared to sham animals but with no differences between the diseased RV and LV. At the stage of decompensation, however, we observed an exclusive downregulation of DUSP1 in the RV of PAB animals. Adeno-associated virus serotype 9 (AAV9) were utilized to overexpress DUSP-1 or GFP (AAV9-control) in the heart in order to reveal its contribution to RHF. Injection of AAV9 (5x1012GC/kg) 1 week and 15 weeks after surgery resulted in an approximately five-fold increase in DUSP-1 expression compared to non-AAV9-DUSP treated animals throughout the study. While no major differences in cardiac function were observed 7 weeks after surgery, at the stage of decompensation (22 weeks after surgery), PAB animals with DUSP-1 overexpression revealed an improved RV function (TAPSE, RV FAC) and lower cardiac BNP expression (PCR, Western blot) and release (ELISA) but comparable PA gradients and RV hypertrophy compared to PAB animals without DUSP-1 overexpression. Sham animals (22 weeks after surgery), however, showed a moderate deterioration in cardiac function in response to chronic DUSP-1 overexpression together with mildly increased BNP (tissue; blood) and cardiac inflammation (cytokine array) compared to sham animals with GFP overexpression or sham animals without AAV9 treatment.
Conclusions
Chronic DUSP-1 overexpression slows down the progression to RVF in PAB rats. However, there appears to be a significant difference in the impact of DUSP-1 overexpression in a system of cardiac stress (PAB) or at baseline (sham). Future studies need to focus on the mechanisms underlying these DUSP-1 effects in RVH and RHF, considering also that nuclear DUSP-1 is thought to have an important role in the feedback loop of MAPKs nuclear signaling.