Abstract: TH-PO436

Eliminating SIRPα Replicates Exercise Induced Remodeling and Prevents Cardiac Dysfunction in CKD

Session Information

Category: Nutrition, Inflammation, and Metabolism

  • 1401 Nutrition, Inflammation, Metabolism

Authors

  • Wu, Jiao, Baylor College of Medicine, Houston, Texas, United States
  • Davogustto, Giovanni, The University of Texas Health Science Center at Houston, Houston, Texas, United States
  • Hu, Zhaoyong, Baylor College of Medicine, Houston, Texas, United States
  • Wang, Yanlin, Baylor College of Medicine, Houston, Texas, United States
  • Taegtmeyer, Heinrich, The University of Texas Health Science Center at Houston, Houston, Texas, United States
  • Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
  • Thomas, Sandhya S., Michael E. Debakey Veteran Affairs Medical Center, Houston, Texas, United States
Background

A major consequence of chronic kidney disease (CKD) is uremic cardiomyopathy characterized by left ventricular hypertrophy (LVH), systolic and diastolic dysfunction. Even at early stages of CKD with near normal GFR, and normal blood pressure, LVH is present, which suggests an unidentified trigger unrelated to pressure overload. We now find that elevations of a novel protein, signal regulatory protein alpha (SIRPα) in CKD cardiac muscle not only adversely influences insulin signaling cardiac fibrosis, but also cardiac dysfunction classically associated with CKD. Suppression of SIRPα reverses CKD-induced cardiac dysfunction and promotes exercise induced cardiac remodeling.

Methods

SIRPα whole body mutant (Mt) mice and wild type mice (WT) were compared after 8 weeks of subtotal nephrectomy. Cardiac function was analyzed in vivo with M-mode and doppler echocardiography. N=8-9 mice/group, results are presented as mean±SD.

Results

Hearts of SIRPα Mt sham mice exhibit eccentric LVH compared with WT sham (LV mass/height 1.532±0.167 vs 1.329±0.216, p=0.04; Relative wall thickness 0.519±0.052 vs 0.608±0.098, p=0.03), preserved systolic function (EF 70.649±6.826 vs 65.901±5.304) as well as diastolic function (E/A 1.812±0.521 vs. 1.499±0.254). However, in WT Sham vs. WT CKD mice there is evidence of cardiac dysfunction characterized by reduced ejection fraction (EF) % (65.901±5.304 vs. 53.112±11.302, p =0.016) and reduced cardiac output (CO) ml/min (19.4±3.942 vs. 15.493±2.474, p=0.03). Doppler analysis revealed diastolic dysfunction in WT CKD as well (E/A: 1.499± 0.254 vs. 1.146±0.102, p=0.008). In WT CKD mice systolic blood pressure was not different than WT sham, suggesting changes observed are not due to pressure overload. On the contrary, in SIRPα Mt mice, induction of CKD did not significantly affect cardiac function (EF 70.649± 6.826 vs. 65.816±2.568, CO: 24.702±3.247 vs. 23.6±5.765, E/A 1.812±0.521 vs. 1.483±0.3, p > 0.05 for all).

Conclusion


In conclusion, suppression of SIRPα replicates exercise induced cardiac remodeling, similar to marathon-runners, as evidenced by eccentric LVH, preserved EF and diastolic function. Furthermore, hearts of SIRPα Mt mice were protected against CKD-induced cardiac dysfunction. Therefore, SIRPα may prove to be a key mediator for prevention of CKD-associated cardiomyopathy.

Funding

  • Other NIH Support