Abstract
Cardiomyocyte‐specific deletion of sarcoglycan‐δ leads to dilated cardiomyopathy, autonomic dysfunction, and exaggerated stress‐induced cardiovascular reactivity
The FASEB journal, Vol.36(S1)
05/2022
DOI: 10.1096/fasebj.2022.36.S1.R2050
Abstract
Deficiency of sarcoglycan‐δ (Sgcd) induces disruption of the dystrophin glycoprotein complex, resulting in loss of membrane stability. We have reported that angiotensin II (AngII)‐mediated autonomic dysfunction precedes and predicts development of dilated cardiomyopathy (DCM) in the global Sgcd‐deficient mice [Exp Physiol 2015].The relative contribution of cardiomyocyte‐targeted Sgcd on DCM and autonomic dysfunction remains unknown. Our goal is to determine whether cardiac remodeling in the Sgcd mutations is an intrinsic process of the cardiomyocytes. We have also observed that global Sgcd‐deficient mice with DCM exhibit anxiety‐like behaviors. AngII via type 1 receptors (AT1R) is well‐known to mediate anxiety‐related behaviors, while Ang‐(1‐7) via Mas receptors is anxiolytic. Thus, we hypothesize that Sgcd in the ventricular myocytes is essential for the progression of DCM, and to elicit emotional stress responses. Cardiac‐specific Sgcd‐deficient (cSgcd‐KO) and littermate control (WT) mice were generated by breeding male αMHCcre+(αmyosin‐heavy chain Myh6 promoter drives expression of the cre‐recombinase) withfemaleglobal Sgcd‐deficientmice. Absence of Sgcdin the cardiomyocytes was confirmed by immunohistochemistry and qPCR in the cSgcd‐KO mice. WT (n=11) and cSgcd‐KO (n=14) mice were echoed every month, from 8 weeks of age, to monitor progression of DCM. At ~35 weeks of age, telemeters (DSI) were implanted to measure changes in blood pressure (BP), heart rate (HR) and locomotor activity during acute emotional stress challenge (20 min exposure to predator odor). Autonomic indices including baroreflex sensitivity (BRS, sequence technique), and resting cardiac vagal and sympathetic tone (HR responses to atropine and propranolol, respectively) were calculated. At 36±1 weeks of age, cSgcd‐KO mice exhibit 62% increase in left ventricular (LV) end‐diastolic volume, 58% decrease in LV ejection fraction, and increased cardiac fibrosis (p<0.05 vs. 10 weeks of age). At baseline, cSgcd‐KO mice exhibit lower BP (100±6 vs.121±1 mmHg), reduced BRS (0.72±0.08 vs.2.01±0.05 ms/mmHg) and vagal tone (∆HR= +32±6 vs. +151±18 bpm), and increased sympathetic tone (∆HR= ‐212±12 vs. ‐123±10 bpm) (p<0.05 vs.WT). Paradoxically, given increased basal sympathetic tone and decreased basal vagal tone, stress caused hypotension in the cSgcd‐KO mice with DCM, likely due to reduced cardiac output. This is accompanied by profound increase in AT1R, and reduced expression of Mas and MrgD receptors (ligand for newly identified heptapeptide alamandine) in LV and brainstem (p<0.0001‐0.01 vs. baseline and WT). We conclude ‐ (i) Sgcddeleted exclusively from the cardiac myocytes creates a novel transgenic mouse strain that develops DCM at ~35 weeks of age. (ii) Stress‐evoked profound changes in CNS and systemic hemodynamics occur directly or indirectly, and cannot be ascribed to Sgcd loss in vascular smooth muscle, endothelium, neurons, or astrocytes. (iii) Contributions of the renin‐angiotensin system is pivotal in pathophysiology of Sgcd deficiencies.
Details
- Title: Subtitle
- Cardiomyocyte‐specific deletion of sarcoglycan‐δ leads to dilated cardiomyopathy, autonomic dysfunction, and exaggerated stress‐induced cardiovascular reactivity
- Creators
- Gabriela Cavazza Cerri - University of IowaLiping Yang - University of IowaKathy Zimmerman - University of IowaAlyssa Bosko - University of IowaMark Chapleau - University of IowaRobert Felder - University of IowaRobert Weiss - University of IowaRasna Sabharwal - University of Iowa
- Resource Type
- Abstract
- Publication Details
- The FASEB journal, Vol.36(S1)
- Publisher
- The Federation of American Societies for Experimental Biology
- DOI
- 10.1096/fasebj.2022.36.S1.R2050
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Number of pages
- 1
- Grant note
- NIH (R01HL149677; S10OD019941)
- Language
- English
- Date published
- 05/2022
- Academic Unit
- Radiology; Iowa Neuroscience Institute; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984230622202771
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