Heart failure and metabolic alterations in cardiomyocyte specific p38MAPK knockout mice after AngiontensinII ‐ treatment

Study objective Analysis of p38MAPKs role in cardiac remodelling in response to AngiotensinII‐signaling as it is still unclear if p38MAPK is rather detrimental or beneficial in this context. Methods p38 flox/flox mice were either crossbred with SM22 alpha ‐ or alpha‐MHC cre‐deleter mice to achieve either a ko in vascular smooth muscle cells and cardiomyocytes (SM22p38) or a tamoxifen inducible cardiomyocyte specific p38MAPK ko (iCMp38). Mice were analyzed in a pressure overload model using AngiotensinII (AngII) (1,5mg/kg/d) over 14 days with echocardiography, telemetric blood pressure measurements, gene expression analysis and histological analysis. Results Telemetric blood pressure measurements of SM22p38 mice showed no significant differences between control and ko at baseline. After administration of Angiotensin II control mice showed an increase in mean arterial pressure from 105±10mmHg to 130±5mmHg which was persistent over the whole application time of 14 days. In ko mice however, this typical AngII‐induced increase in blood pressure occurred only during the first 4–6 hours of AngII‐treatment and dropped then dramatically to 86±13 mmHg. Cardiac function, measured by ejection fraction (EF), end diastolic (EDV) and end systolic volume (ESV) was comparable between control and ko mice in both mouse strains under baseline conditions (SM22p38: EF: ctrl.: 60 ± 7%, ko: 57 ± 12%, EDV: Ctrl.: 75 ± 11 μl, KO: 82 ± 17 μl, ESV: ctrl.: 30 ± 8 μl, ko: 37 ± 18 μl; iCMp38: EF: ctrl: 58 ±2%, ko: 59±11%, EDV: ctrl: 80±13μl, ko: 90±20μl, ESV: ctrl: 34±6μl, ko: 40±20μl, ). However, after 48 hours of AngII‐treatment ko mice of both models showed a severe cardiac dilation and a dramatic reduction in systolic pump function (SM22p38: EF: ctrl.: 50±7%, ko: 20 ±3%, EDV: ctrl: 79±8μl, ko: 122 ±22μl, ESV: ctrl.: 40±7μl, ko: 98±17μl; iCMp38: EF: ctrl.: 49±12%, ko: 29±8%, EDV: ctrl: 77±10 μl, ko: 110±15μl, ESV: ctrl.: 39±9μl, ko: 78±16μl). Closer investigation of the timeline in iCMp38 KO mice revealed that both, control and ko mice showed a reduced pump function after 12 hours of AngII (EF: ctrl.: 36±3%, kO: 33±6%). But while control mice were able to recover and reach their original cardiac function after 48 hours, ko mice were still highly impaired in systolic pump function and showed also a cardiac dilation with increased EDV and ESV. Global cardiac gene expression analysis was performed using a microarray approach at baseline and after 48 hours of AngII. This showed only minor changes in cardiac gene expression at baseline but significant alterations between control and p38 ko mice after 48 hours of AngII‐treatment (8162 differentially expressed genes, p<0.01). Among these were several cytokines as IL6 and IL1β highly upregulated, as well as chemokines as Cxcl 5, 1 and Ccl2 and their receptor Cxcr2. Further deregulations affected genes of cardiac metabolism. We found genes of glucose uptake and utilization as well as fatty acid utilization to be downregulated. Also pyruvate dehydrogenase (PDH) seemed to be inhibited as PDH‐kinase 4 was highly up (5x) and PDH‐phosphatase highly downregulated (7x) indicating a major metabolic limitation in ko hearts. Conclusion Our data point to a special role of p38MAPK in the early phase of cardiac remodeling in response to pressure overload. Thereby, p38 MAPK seems to play a newly discovered role in cardiac metabolism and inflammation.