Abstract 252: Downregulated Striated Muscle Preferentially Expressed Protein Kinase Enhances Susceptibility to Post-Operative Atrial Fibrillation
| Autor: | Na Li, Zachary Donoviel, Ann P. Quick, Katherina M. Alsina, Issam Abu-Taha, Xander H.T. Wehrens, Julia O. Reynolds, Hannah M. Campbell, Li Ni, Tina Veleva, Dobromir Dobrev |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Circulation Research. 123 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Post-operative atrial fibrillation (poAF) is the most common perioperative arrhythmia associated with increased hospital morbidity and mortality. It is known that atrial myocyte Ca 2+ handling changes can play a crucial role in AF pathogenesis, although the specific mechanisms involved in poAF have not been elucidated. Our lab has previously identified Striated Muscle Preferentially Expressed Protein Kinase (SPEG) as a binding partner of the major cardiac Ca 2+ release channel RyR2 and its negative regulator JPH2, which are critical for cardiac Ca 2+ homeostasis. We hypothesized that decreased SPEG levels may create an arrhythmogenic substrate promoting poAF development. SPEG protein and mRNA levels were assessed using Western blotting and qRT-PCR, respectively. To establish a mouse model of poAF, we performed thoracotomy in C57Bl/6J mice followed by rapid atrial pacing three days post-operatively to assess for poAF susceptibility. To test for a cause-effect relationship between decreased SPEG and AF susceptibility, we used a cardiac specific tamoxifen-inducible SPEG conditional knockout (cKO) mouse. Rapid atrial pacing was performed in SPEG cKO mice two weeks post-tamoxifen injection prior to onset of heart failure as assessed by echocardiography. In human atrial samples from patients with poAF we found 41±9% lower SPEGβ mRNA expression (n=7, p=0.04) compared to patients with normal sinus rhythm (NSR, n=8), while SPEGα expression was unchanged. Similarly, SPEGβ protein was 45±7% lower in poAF vs NSR patients (n=6, p=0.04). In contrast, SPEGβ mRNA expression was not decreased in patients with persistent or paroxysmal AF. Similar to poAF patients, our novel mouse model exhibited 90±4% lower SPEGβ protein levels (n=4, p=0.03) compared to mice with NSR (n=4) after rapid atrial pacing three days post-thoracotomy. Furthermore, SPEG cKO mice had increased AF duration after rapid atrial pacing (19.43 ± 15.16 s, n=3) compared to controls (0.27 ± 0.27 s, n=6, p=0.01), suggesting that loss of SPEG is sufficient to drive AF. In conclusion, we discovered reduced SPEGβ mRNA and protein in both humans and mice with poAF and established that a loss of SPEG might causally contribute to poAF pathogenesis. |
| Databáze: | OpenAIRE |
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