Portal de investigação
The adult heart requires baseline expression of the transcription factor Hand2 to withstand right ventricular pressure overload
Data de publicação:
Data Ahead of Print:
Autores da FMUP
Participantes de fora da FMUP
- Videira, RF
- Koop, AMC
- Ottaviani, L
- Poels, EM
- Kocken, JMM
- Dos Remedios, C
- Van de Kolk, KW
- Sarvaas, GJD
- Llucia Valldeperas, A
- Nascimento, D.
- De Windt, LJ
- De Man, FS
- Berger, RMF
- Martins, PAD
Unidades de investigação
Abstract
Aims Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV). Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a 'foetal gene programme' contributing to pathological cardiac remodelling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodelling in response to pressure overload induced by pulmonary artery banding (PAB). Methods and results In this study, Hand2(F/F) and MCM- Hand2(F/F) mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived haemodynamic parameters as well as molecular remodelling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control-banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV pressure-overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass, and impaired cardiac function. RNA-sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. Conclusion Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressu re overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.
Dados da publicação
- ISSN/ISSNe:
- 1755-3245, 0008-6363
- Tipo:
- Article
- Páginas:
- 2688-2702
- DOI:
- 10.1093/cvr/cvab299
- Link para outro recurso:
- www.scopus.com
Cardiovascular Research Oxford University Press
Citações Recebidas na Web of Science: 1
Citações Recebidas na Scopus: 5
Documentos
- Não há documentos
Filiações
Keywords
- Right ventricle remodelling; Hand2; Transcriptional regulation; Heart failure
Financiamento
Proyectos asociados
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Remodelling adversely impacts arrhythmic outcome following isolated aortic valve replacement surgery
Investigador Principal: Inês Maria Falcão Sousa Pires Marques
Estudo Clínico Académico (Remodelling) . 2020
New physiological mechanisms, diagnostic and therapeutic approaches in heart failure with preserved ejection fraction.
Investigador Principal: André Pedro Leite Martins Lourenço
Estudo Clínico Académico . 2021
The Heart under Pressure: Mechanisms underlying HEpEF Secondary to chronic pressure Overload or Metabolic Syndrome
Investigador Principal: Inês Maria Falcão Sousa Pires Marques
Estudo Clínico Académico . 2020
Citar a publicação
Videira RF,Koop A,Ottaviani L,Poels EM,Kocken JMM,Dos C,Mendes P,Van de Kolk KW,Sarvaas GJD,Louren?o A,Llucia A,Nascimento D,De Windt LJ,De Man FS,Falcao I,Berger RMF,Martins P. The adult heart requires baseline expression of the transcription factor Hand2 to withstand right ventricular pressure overload. Cardiovasc. Res. 2022. 118. (12):p. 2688-2702. IF:10,800. (1).
