Insulin-like growth factors and neonatal cardiomyocyte development: ventricular gene expression and membrane receptor variations in normotensive and hypertensive rats

doi:10.1016/0303-7207(89)90076-2

Molecular and Cellular Endocrinology

Volume 63, Issues 1–2, May 1989, Pages 1-14

https://doi.org/10.1016/0303-7207(89)90076-2 Get rights and content

Abstract

Defined factors regulating or influencing mammalian ventricular myocyte (cardiomyocyte) development are not known at this time. During early neonatal ventricular growth, cardiomyocytes begin a ‘transition phase’ of development toward cellular maturation (hypertrophy) that entails terminal proliferation and cellular binucleation. Insulin-like growth factor-I and -II (IGFs) are believed to play a major role in mammalian postnatal and fetal growth, possibly functioning in local environments which facilitate autocrine or paracrine tissue growth characteristics. Therefore, we examined the expression of the IGF genes and their corresponding membrane receptors in ventricles of normotensive and spontaneously hypertensive (SHR) rat pups during the first 7–14 days of age. We have determined: (1) by receptor crosslinking that neonatal ventricular membranes possess type 1 and type 2 IGF receptors; (2) by receptor binding analysis that type 1 IGF receptor concentration is elevated between days 1–7 in the SHR and shows an age-related decline in concentration and an increase in affinity in both strains; (3) by Northern blot analysis that neonatal rat ventricular tissue expresses primarily IGF-II RNA transcripts of 3.6, 2.3 and 1.7 kilobases (kb) in size, with low levels of IGF-I transcripts detected; (4) by slot-blot hybridization that SHR ventricles contain higher levels of IGF-II transcripts at 3 days of age; and (5) localized the IGF transcripts to ventricular myocytes by tissue in situ hybridization. These observations support a role for cardiomyocyte-produced IGFs that may be locally produced and act in an autocrine or paracrine fashion to modulate cardiomyocyte growth and maturation in the developing rat heart. Because both IGF receptor and IGF RNA transcript parameters differed in SHR hearts, genetically predisposed to hypertrophy, a potentially important biochemical alteration may be associated with the fetal/neonatal growth abnormalities of the developing heart in this rat strain.

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Although, this may provide preliminary compensatory hypertrophic response to the stress, prolonged hypertrophic insults may subsequently lead to maladaptive responses. Under pathological conditions like hypertension, the levels of IGF-II, IGF-I and their receptors are found to be modulated (Engelmann et al., 1989; Feng et al., 2018) and particularly the IGF-II/IGFIIR signalling has been shown to be associated with the development of cardiac hypertrophy with an increase in the levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) via Gαq activation. Interestingly, the IGF-II growth factor binds to both IGFIR and IGFIIR but with different affinity (Blyth et al., 2020).
Cardiovascular diseases are caused by multitudes of stress factors like hypertension and their outcomes are associated with high mortality and morbidity worldwide. Nerolidol, a naturally occurring sesquiterpene found in several plant species, embodies various pharmacological benefits against numerous health disorders. However, their effects on hypertension induced cardiac complications are not completely understood.
The present study is to elucidate the efficacy of nerolidol against hypertension related cardiac hypertrophy in spontaneously hypertensive rats (SHRs).
For preliminary in vitro studies, H9c2 cardiomyoblasts cells were challenged with 200 nM Angiotensin-II (AngII) for 12 h and were then treated with nerolidol for 24 h. The hypertrophic effect in H9c2 cells were analyzed by actin staining and the modulations in hypertrophic protein markers and mediators were determined by Western blotting analysis. For in vivo experiments, sixteen week-old male Wistar Kyoto (WKY) and SHRs were segregated into five groups (n = 9): Control WKY, hypertensive SHRs, SHRs with low dose (75 mg/kg b.w/day) nerolidol, SHRs with high dose (150 mg/kg b.w/day) nerolidol and SHR rats treated with an anti-hypertensive drug captopril (50 mg/kg b.w/day). Nerolidol treatment was given orally for 8 weeks and were analysed through Echocardiography. After euthanasia, hematoxylin and eosin staining, Immunohistochemical analysis and Western blotting was performed on left ventricle tissue.
Western blotting analysis revealed that nerolidol significantly attenuates AngII induced expression of hypertrophic markers ANP and BNP in H9c2 cardiomyoblasts. In addition, actin staining further ascertained the potential of nerolidol to ameliorate AngII induced cardiac hypertrophy. Moreover, nerolidol administration suppressed the hypertrophic signalling mediators like calcineurin, GATA4, Mel-18, HSF-2 and IGFIIR in a dose-dependent fashion. In silico studies also ascertained the role of Mel-18 in the ameliorative effects of nerolidol. Further, these intriguing in vitro results were further confirmed in in vivo SHR model. Oral neraolidol in SHRs efficiently reduced blood pressure and ameliorated hypertension induced cardiac hypertrophic effects by effectively reducing the levels of proteins involved in cardiac MeL-18-HSF2-IGF-IIR signalling.
Collectively, the data reveals that the cardioprotective effect of nerolidol against hypertension induced hypertrophy involves reduction in blood pressure and regulation of the cardiac Mel-18-IGFIIR signalling cascade.
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It has been reported that the cross-talk between IGF2R signals and the small G-protein Gαi regulates cell behavior by activating specific intracellular signaling cascades in a pertussis toxin-sensitive manner (Hawkes et al., 2006; McKinnon et al., 2001; Nishimoto et al., 1987). It has been reported that IGF-IIR was over expression induced by TNF-α, LPS, ANGII, inomycin in H9c2 cells and age dependently in SHR hearts (Chu et al., 2011; Engelmann et al., 1989) and the myocardial infarction tissue of human (Chu et al., 2008). We also found that IGF-IIR activation is associated with the progression of pathological hypertrophy in the abdominal aorta ligation rat mode (Lee et al., 2006).
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Dung-shen (Codonopsis pilosula) attenuated the cardiac-impaired insulin-like growth factor II receptor pathway on myocardial cells
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IGFII plays a role in mammalian postnatal and foetal growth functioning in an autocrine or paracrine manner. SHR rats display high levels of ventricular and heart IGFII and IGFIIR, and low levels of IGFI mRNA and protein expression during foetal, neonatal and postnatal periods (Engelmann, Boehm, Haskell, Khairallah, & Ilan, 1989; Ghosh, Dahms, & Kornfeld, 2003), whereas limb, muscle, lungs, intestine, kidneys, liver and brain vary in degree of low IGFIIR mRNA concentration (Brown et al., 1986). However, IGFII expression declines after birth and it goes through a transition during the neonatal stage (Engelmann et al., 1989).
Previous studies from our lab showed that increase in AngII in H9c2 cells causes elevated IGFII and IGFIIR through MEK and JNK, leading to rise in intracellular calcium, calcineurin activation by PLC-β3 via Gαq, insertion into mitochondrial membranes of Bad, and apoptosis via caspases 9 and 3. Codonopsis pilosula is traditionally used to lower blood pressure. The purpose of our study is to investigate if C. pilosula attenuates AngII plus Leu²⁷-IGFII-induced calcium influx and apoptosis in H9c2 cardiomyoblasts. C. pilosula significantly attenuated AngII induced IGFIIR promoter activity. Leu²⁷-IGFII was applied to enhance the AngII effect. C. pilosula also reversed Ca²⁺ influx, MOMP and apoptosis increased by AngII plus Leu²⁷-IGFII. Molecular markers in IGFIIR apoptotic pathway (IGFIIR, calcineurin, etc.) and IGFIIR-Gαq association were downregulated by C. pilosula. However, p-Bad^Ser136 and Bcl-2 were increased. Therefore, C. pilosula suppresses AngII plus Leu²⁷-IGFII-induced IGFII/IGFIIR pathway in myocardial cells.
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The insulin-like growth factors (IGFs) have a regulatory function in fetal cardiac development [1].
The insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and human growth hormone (h-GH) have been recognized as therapeutic targets for the heart disease therapy. The bioavailability and actions of insulin-like growth factors-II (IGF-II) and matrix metalloproteinase-9 (MMP9) are important for embryonic development and cardiomyocyte differentiation as well. However, the clinical manifestations following the change in the serum IGF-II and MMP9 in infants with isolated ventricular septal defect (VSD) undergoing surgical repair have not been clearly defined.
Serum samples were collected from 72 infants: Twenty normal infants (group I) and 51 consecutive infants with echocardiography established isolated VSD (aged from 3 months to 1 year) were investigated. Among the 51 infants with VSD, 28 with shunt fraction, Qp/Qs< or = 1.5 were free of congestive heart failure symptoms (group II); 23 with shunt fraction, Qp/Qs> or = 2.0 were in congestive heart failure (group IIIa); and 23 of these 23 infants had undergone VSD repair 6 months before their second study (group IIIb). All insulin-like growth factors-II (IGF-II) and human growth hormone (h-GH), insulin like growth factor binding protein-3 (IGFBP-3) and its specific serum protease-MMP9 concentration were analyzed using ELISA and zymography, respectively.
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Research paperInsulin-like growth factors and neonatal cardiomyocyte development: ventricular gene expression and membrane receptor variations in normotensive and hypertensive rats

Abstract

Biochem. Biophys. Res. Commun.

Cell Differ.

J. Biol. Chem.

J. Mol. Cell. Cardiol.

Dev. Biol.

J. Mol. Cell. Cardiol.

Gene Anal. Tech.

J. Biol. Chem.

J. Biol. Chem.

Resp. Physiol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Clin. Endocrinol. Metab.

Circ. Res.

Am.J. Physiol.

Endocrinology

Endocrinology

Development

Annu. Rev. Biochem.

Biochemistry

Biochem.J.

Lab. Invest.

Cell Tissue Kinet.

Am. J. Physiol.

Circ. Res.

Circ. Res.

Endocrinology

Annu. Rev. Physiol.

Biol. Neonate

Research paper
Insulin-like growth factors and neonatal cardiomyocyte development: ventricular gene expression and membrane receptor variations in normotensive and hypertensive rats