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| Item Type: | Article |
|---|---|
| Title: | Hemodynamic stress-induced cardiac remodelling is not modulated by ablation of phosphodiesterase 4D interacting protein |
| Creators Name: | Mohamed, B.A. and Elkenani, M. and Mobarak, S. and Marques Rodrigues, D. and Annamalai, K. and Schnelle, M. and Bader, M. and Hasenfuss, G. and Toischer, K. |
| Abstract: | Adrenergic stimulation in the heart activates the protein kinase A (PKA), which phosphorylates key proteins involved in intracellular Ca(2+) handling. PKA is held in proximity to its substrates by protein scaffolds, the A kinase anchoring proteins (AKAPs). We have previously identified the transcript of phosphodiesterase 4D interacting protein (Pde4dip; also known as myomegalin), one of the sarcomeric AKAPs, as being differentially expressed following hemodynamic overload, a condition inducing hyperadrenergic state in the heart. Here, we addressed whether PDE4DIP is involved in the adverse cardiac remodelling following hemodynamic stress. Homozygous Pde4dip knockout (KO) mice, generated by CRISPR-Cas9 technology, and wild-type (WT) littermates were exposed to aortocaval shunt (shunt) or transthoracic aortic constriction (TAC) to induce hemodynamic volume overload (VO) or pressure overload (PO), respectively. The mortality, cardiac structure, function and pathological cardiac remodelling were followed up after hemodynamic injuries. The PDE4DIP protein level was markedly downregulated in volume-overloaded- but upregulated in pressure-overloaded-WT hearts. Following shunt or TAC, mortality rates were comparably increased in both genotypes. Twelve weeks after shunt or TAC, Pde4dip-KO animals showed a similar degree of cardiac hypertrophy, dilatation and dysfunction as WT mice. Cardiomyocyte hypertrophy, myocardial fibrosis, reactivation of cardiac stress genes and downregulation of ATPase, Ca(2+) transporting, cardiac muscle, slow twitch 2 transcript did not differ between WT and Pde4dip-KO hearts following shunt or TAC. In summary, despite a differential expression of PDE4DIP protein in remodelled WT hearts, Pde4dip deficiency does not modulate adverse cardiac remodelling after hemodynamic VO or PO. |
| Keywords: | Cardiac Remodelling, PKA Compartmentalization, Pressure Overload, Volume Overload, Animals, Mice |
| Source: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-1838 |
| Publisher: | Wiley |
| Volume: | 26 |
| Number: | 16 |
| Page Range: | 4440-4452 |
| Date: | August 2022 |
| Official Publication: | https://doi.org/10.1111/jcmm.17468 |
| PubMed: | View item in PubMed |
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