Beneficial effects of paricalcitol on cardiac dysfunction and remodelling in a model of established heart failure

Autor: Laura Martín-Nunes, Maria José G.M‐Piedras, María Fernández-Velasco, Almudena Val-Blasco, Patricia Prieto, Gema Ruiz-Hurtado, María Tamayo, Eduardo Lage, Carmen Delgado, José Alberto Navarro-García
Přispěvatelé: Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), UAM. Departamento de Tecnología Electrónica y de las Comunicaciones
Rok vydání: 2020
Předmět:
Zdroj: DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria
instname
Digital.CSIC. Repositorio Institucional del CSIC
DDFV: Repositorio Institucional de la Universidad Francisco de Vitoria
Universidad Francisco de Vitoria
Br J Pharmacol
Biblos-e Archivo. Repositorio Institucional de la UAM
Biblos-e Archivo: Repositorio Institucional de la UAM
Universidad Autónoma de Madrid
ISSN: 1476-5381
0007-1188
DOI: 10.1111/bph.15048
Popis: [Background and Purpose]: The synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of paricalcitol associated with the VDR pathway, less information is available about the structural and functional cardiac effects of paricalcitol on established heart failure (HF) and particularly its effects on associated electrophysiological or Ca2+ handling remodelling.
[Experimental Approach]: We used a murine model of transverse aortic constriction (TAC) to study the effect of paricalcitol on established HF. Treatment was initiated 4 weeks after surgery over five consecutive weeks, and mice were sacrificed 9 weeks after surgery. Cardiac MRI (CMRI) was performed 4 and 9 weeks after surgery. Hearts were used for biochemical and histological studies and to isolate ventricular myocytes for electrophysiological and calcium imaging studies.
[Key Results]: CMRI analysis revealed that, compared with vehicle, paricalcitol treatment prevented the progression of ventricular dilation and hypertrophy after TAC and halted the corresponding decline in ejection fraction. These beneficial effects were related to the attenuation of intracellular Ca2+ mishandling remodelling, antifibrotic and antihypertrophic effects and potentially antiarrhythmic effects by preventing the reduction of K+ current density and the long QT, JT and TpTe intervals observed in HF animals.
[Conclusion and Implications]: The results suggest that paricalcitol treatment in established HF hampers disease progression and improves adverse electrophysiological and Ca2+ handling remodelling, attenuating the vulnerability to HF‐associated ventricular arrhythmias. Paricalcitol may emerge as a potential therapeutic option in the treatment of HF.
This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2014‐57190R and SAF2017‐84777‐R), Instituto de Salud Carlos III (ISCIII) (PI17/01093 and PI17/01344), European Regional Developmentc Fund (FEDER), Sociedad Española de Cardiología (SEC) and Centro de Investigación Biomédica en Red Cardiovascular (CIBER‐CV), a network funded by ISCIII. M.F.‐V. is a Miguel Servet II researcher of ISCIII (MSII16/00047 Carlos III Health Institute). G.R.‐H. is a Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). M.T. is a predoctoral fellow of the Spanish Ministry of Science, Innovation and Universities (Ministerio de Ciencia e Innovación) (FPU‐17/06135).
Databáze: OpenAIRE
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