Abstract
Insulin and insulin-like growth factor stimulate protein synthesis and cardioprotection in the heart, acting through their receptors (INSRs, IGF1Rs) and signalling via protein kinase B (PKB, also known as Akt). Protein synthesis is increased in hearts perfused at alkaline pHo to the same extent as with insulin. Moreover, α1-adrenergic receptor (α1-AR) agonists (e.g. phenylephrine) increase protein synthesis in cardiomyocytes, activating PKB/Akt. In both cases, the mechanisms are not understood. Our aim was to determine if insulin receptor-related receptors (INSRRs, activated in kidney by alkaline pH) may account for the effects of alkaline pHo on cardiac protein synthesis, and establish if α1-ARs signal through the insulin receptor family. Alkaline pHo activated PKB/Akt signalling to the same degree as insulin in perfused adult male rat hearts. INSRRs were expressed in rat hearts and, by immunoblotting for phosphorylation (activation) of INSRRs/INSRs/IGF1Rs, we established that INSRRs, together with INSRs/IGF1Rs, are activated by alkaline pHo. The INSRR/INSR/IGF1R kinase inhibitor, linsitinib, prevented PKB/Akt activation by alkaline pHo, indicating that INSRRs/INSRs/IGF1Rs are required. Activation of PKB/Akt in cardiomyocytes by α1-AR agonists was also inhibited by linsitinib. Furthermore, linsitinib inhibited cardiomyocyte hypertrophy induced by α1-ARs in cultured cells, reduced the initial cardiac adaptation (24 h) to phenylephrine in vivo (assessed by echocardiography) and increased cardiac fibrosis over 4 days. We conclude that INSRRs are expressed in the heart and, together with INSRs/IGF1Rs, the insulin receptor family provide a potent system for promoting protein synthesis and cardioprotection. Moreover, this system is required for adaptive hypertrophy induced by α1-ARs.
Highlights
Cardiac muscle contains terminally differentiated cardiomyocytes for contraction, a dense network of capillaries for efficient delivery of oxygen and nutrients, and resident fibroblasts providing extracellular matrix to maintain a robust structure
We identified a novel signalling paradigm in cardiomyocytes in which α1-adrenergic receptor (AR) transactivate insulin receptor family members leading to activation of protein kinase B (PKB)/Akt and extracellular signal-regulated kinases 1/2 (ERK1/2)
As in previous studies [17], alkaline pHo increased protein synthesis in Langendorff perfused rat hearts (Figure 1A); this was significantly inhibited by the phosphoinositide kinase (PI3K) inhibitor, LY294002 (50 mM)
Summary
Cardiac muscle contains terminally differentiated cardiomyocytes for contraction, a dense network of capillaries for efficient delivery of oxygen and nutrients, and resident fibroblasts providing extracellular matrix to maintain a robust structure. Cardiomyocyte hypertrophy is associated with increased protein synthesis to facilitate cell growth, and cytoprotective systems are required to prevent cell death. Two key signalling pathways drive many of these changes: (i) PKB/Akt signalling is cytoprotective and increases protein synthesis [4,5]; (ii) the extracellular signal-regulated kinases 1/2 (ERK1/2) promote translation and confer cytoprotection [5], but are important in effecting changes in gene expression during cardiomyocyte hypertrophy [3,6,7]. Gq protein-coupled receptors (GqPCRs) such as α1-adrenergic receptors (α1-ARs) promote cardiomyocyte hypertrophy, and α1-AR agonists (e.g. phenylephrine or the selective α1A-AR agonist A61603) potentially prevent cardiac maladaptation [8]. These agonists activate both ERK1/2 and PKB/Akt in cardiomyocytes [9]
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