Gαq Protein Carboxyl Terminus Imitation Polypeptide GCIP-27 Improves Cardiac Function in Chronic Heart Failure Rats

Abstract

BackgroundGαq protein carboxyl terminus imitation polypeptide (GCIP)-27 has been shown to alleviate pathological cardiomyocyte hypertrophy induced by various factors. Pathological cardiac hypertrophy increases the morbidity and mortality of cardiovascular diseases while it compensates for poor heart function. This study was designed to investigate the effects of GCIP-27 on heart function in rats with heart failure induced by doxorubicin.Methods and ResultsForty-eight rats were randomly divided into the following six groups receiving vehicle (control), doxorubicin (Dox), losartan (6 mg/kg, i.g.) and three doses of GCIP-27 (10, 30, 90 μg/kg; i.p., bid), respectively. Heart failure was induced by Dox, which was administered at a 20 mg/kg cumulative dose. After 10 weeks of treatment, we observed that GCIP-27 (30, 90 μg/kg) significantly increased ejection fraction, fraction shortening, stroke volume and sarcoplasmic reticulum Ca2+ ATPase activity of Dox-treated hearts. Additionally, GCIP-27 decreased myocardial injury, heart weight index and left ventricular weight index, fibrosis and serum cardiac troponin-I concentration in Dox-treated mice. Immunohistochemistry, western blotting and real-time PCR experiments indicated that GCIP-27 (10–90 μg/kg) could markedly upregulate the protein expression of myocardial α-myosin heavy chain (MHC), Bcl-2, protein kinase C (PKC) ε and phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 as well as the mRNA expression of α-MHC, but downregulated the expression of β-MHC, Bax and PKC βII, and the mRNA expression levels of β-MHC in Dox-treated mice. It was also found that GCIP-27 (30, 90 μg/L) decreased cell size and protein content of cardiomyocytes significantly in vitro by comparison of Dox group.ConclusionsGCIP-27 could effectively ameliorate heart failure development induced by Dox. PKC–ERK1/2 signaling might represent the underlying mechanism of the beneficial effects of GCIP-27.

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

“…These findings strongly support the idea that Pyr3 prevents DOX-induced Nox2 upregulation by disrupting the TRPC3-Nox2 complex formation. Other approaches that reportedly prevent or mitigate DOX-induced dilated cardiomyopathy include exercise (37); treatment with cilostazol (39), an inhibitor of phosphodiesterase type 3 (PDE3), antioxidants (10), or iron chelators (40); and expression of Gα q -inhibitory peptide in cardiomyocytes (41). We previously observed that inhibition OF PDE3 (42) or Gα q -mediated phosphatidylinositol turnover (22) attenuates TRPC3/6 channel activity, and we observed here that exercise reduces TRPC3 expression in mouse hearts ( Figure 7I).…”

Triptolide Upregulates Myocardial Forkhead Helix Transcription Factor p3 Expression and Attenuates Cardiac Hypertrophy

“…Neonatal rat ventricular myocytes (NRVM) from 1 to 2 days old Sprague-Dawley rats were isolated and cultured as described previously (Yang et al, 2013; Lu et al, 2015). After being cultured in serum-free DMEM for 24 h, the cells were incubated for 24 h in a non-serum medium containing 1 μmol/L AngII.…”

The Development of a Stable Peptide-Loaded Long-Acting Injection Formulation through a Comprehensive Understanding of Peptide Degradation Mechanisms: A QbD-Based Approach

“…One such peptide, ACTY116 (the structure is shown in Figure 1 ), comprising 29 amino acids (C 157 H 256 N 40 O 45 , with a molecular weight of 3424 g/mol), was designed in our laboratory as a competitive ligand for the binding sites on Gαq (the activated α subunit of the heterotrimeric G protein) in cardiomyocytes. Extensive investigations have been undertaken concerning the structural design of the peptide and the antihypertrophic evaluation of both GCIP (Gαq protein carboxyl terminus imitation peptide) and ACTY116 (an analog of GCIP with specific structural modification) [ 1 , 2 , 3 ]. These studies have shown that ACTY116 holds considerable promise as a potential drug candidate for advancing into clinical development.…”