2 research outputs found
Downregulation of G protein-coupled receptor kinase 2 levels enhances cardiac insulin sensitivity and switches on cardioprotective gene expression patterns
G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signalling. GRK2
downregulation improves insulin sensitivity and prevents systemic insulin resistance (IR). Cardiac GRK2 levels are increased in
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human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the
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deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore,
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we have explored the interconnections among a systemic IR status, GRK2 dosage and cardiac insulin sensitivity in adult (9 month-old)
animals. GRK2+/- mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function.
Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy,
while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find
that cardiac GRK2 levels increase in situations where IR develops, such as in ob/ob mice or after high fat diet feeding. Our data
suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as IR, diabetes or
obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.Grants from Ministerio de EducaciĂłn y Ciencia (SAF2011-23800), FundaciĂłn para la InvestigaciĂłn
MĂ©dica Aplicada (FIMA) and UTE project CIMA, The Cardiovascular Network of Ministerio Sanidad y Consumo-Instituto Carlos III
(RD06-0014/0037 and RD12/0042/0012), Comunidad de Madrid (S2010/BMD-2332) and EFSD-Novo Nordisk to F.M and UAM
Grupo Santander to C.M and Wood-Whelan Research Fellowship from IUBMB to E.L. We also acknowledge institutional support
from FundaciĂłn RamĂłn Arece