Diastolic Dysfunction is Generated in Mice with Knockout of Smoothelin‐like 1 Protein
Notice bibliographique
Résumé
BACKGROUND Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Ultimately, heart failure (HF) is the common final outcome for most patients with CVD, and HF with preserved ejection fraction (HFpEF) has gained increasing prevalence. Clinical evidence associates HFpEF with microvascular dysfunction and endothelial inflammation, which in turn drive pathologic cardiac remodeling. No therapeutics are available for improving outcomes of HFpEF patients; thus, further research is required to better understand its etiology since the molecular pathways leading to HFpEF are not confined to one pathology. Of particular note, our recent experiments reveal a novel role for the smoothelin‐like 1 (SMTNL1) protein in the endothelium which when disturbed drives dramatic alterations in systemic inflammation, endothelial functional responses, and cardiovascular performance. OBJECTIVE The study examined the impact of SMTNL1 deficiency on cardiac function in male murine models. METHODS SMTNL1 global knockout (KO) mice (10‐week old, young male) were anesthetized by isoflurane and underwent M‐mode echocardiographic (ECG) imaging (Vevo770, Visual Sonics, Canada), followed by left ventricular (LV) catheterization (PVR 1045, Millar Instruments, Houston, TX) and pressure‐volume (PV) loop measurements to assess the systolic‐diastolic and hemodynamic parameters of cardiac function. The background strain 129S6 wildtype (WT) mice served as the control group. Mice were terminated at the end of PV loop procedures, and serum was collected for detection of circulating markers (Luminex array, EveTechnologies Inc.). RESULTS Gross dissection revealed distinct cardiac morphology; hearts from KO animals were significantly smaller than WT littermates (~12% smaller HM:TL ratios), but the proportion of heart mass taken up by LV was greater (~10% larger LV:HM ratios). The non‐invasive ECG analysis of KO mice showed normal ejection fraction (%EF: 54.5±3.3 vs 44.0±3.0) and fractional shortening (%FS: 28.2±2.2 vs 21.7±1.7) relative to the WT counterparts. However, PV loop analysis revealed diastolic dysfunction with significantly increased end diastolic pressure (EDP: 11.6±1.7 vs 4.9±1.8 mmHg, p<0.05) and LV relaxation time (Tau; 11.7±0.4 vs 7.0±0.4 ms, p<0.0001) along with a steeper end diastolic PV relationship (EDPVR: 0.55±0.14 vs 0.22±0.06, p<0.05) an indicator of stiffer heart, in KO group when compared to the WT group. Additionally, circulating serum markers such as sE‐selectin and pro‐MMP9 were elevated in the KO mice. CONCLUSION In the present study, we have identified intriguing linkages for SMTNL1 and pathophysiological definitions of diastolic dysfunction, and suggest SMTNL1 knockout animals represent a new pre‐clinical model to examine the development of HF‐pEF. However, the pathophysiological role of SMTNL1 protein in the regulation of cardiac hemodynamics, potentially through endothelial inflammation and microvascular dysfunction requires further study. Support or Funding Information ‐Libin Cardiovascular Institute of Alberta, University of Calgary ‐Achievers in Medicine Scholarship from Cumming School of Medicine, University of Calgary ‐CIHR Travel award This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
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