G.ALPHA.q-Protein Carboxyl Terminus Imitation Polypeptide GCIP-27 Attenuates Proliferation of Vascular Smooth Muscle Cells and Vascular Remodeling in Spontaneously Hypertensive Rats

Abstract

Vascular hypertrophy and remodeling are adaptive structural changes in response to sustained increases in arterial pressure or altered shear stress.1) These structural changes, which occur in various clinical disorders including hypertension, atherosclerosis, and restenosis after balloon angioplasty not only play critical roles in the pathogenic mechanisms of these conditions but are also key targets for treating such diseases. 2)Accumulating evidence indicates that various Gq proteincoupled receptor ligands such as noradrenaline (NA), angiotensin II (Ang II), endothelin-1 (ET-1), neuropeptide Y (NPY), and vasopressin can trigger hypertrophic responses in cultured vascular smooth muscle cells (VSMC) and vascular remodeling in vivo. [1][2][3][4][5][6] These neurohumoral factors induce vascular hypertrophy and remodeling through hemodynamic and direct non-hemodynamic pathways that are related closely to Gq signaling. These findings are consistent with the conclusion that Gq protein and its downstream molecules play vital roles in signal transduction pathway inducing vascular remodeling; Gq protein is thought to locate at the convergent point. Although some antihypertensive agents such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blocking agents (ARBs), can alleviate vascular hypertrophy and remodeling to some extent, the effects of these drugs with a single target are limited due to compensatory secretion of other Gq protein-coupled receptor ligands.7) Theoretically, targeting the Gq signaling pathway may have more satisfactory effect on vascular remodeling therapy. In the heterotrimetic G protein, the carboxyl terminus of a-subunit is surface exposed and easily accessible for contacting the receptor protein, so the C-terminal portion of Ga is critical for the specificity of G-protein-coupled receptor.8-10) Therefore inhibition of Gaq signaling may be an approach to prevent vascular remodeling from overloaded pressure and other pathological stimuli.Gaq protein carboxyl terminus imitation polypeptide (GCIP), a peptide cloned and constructed in our laboratory, is able to inhibit cardiomyocyte hypertrophy induced by NA in vitro. 11) GCIP-27, the optimized form of GCIP, could prevent hypertrophic responses in cultured rat cardiomyocytes induced by NA or Ang II, inhibited left ventricular hypertrophy induced by NA in mice and rats and that induced by suprarenal abdominal aortic stenosis in rats, as well as right ventricular hypertrophy induced by monocrotaline. [12][13][14] However, little is known about the effect of GCIP-27 on vascular remodeling. Because the pathophysiological process of vascular remodeling is quite complex and may include unique elements not observed in cardiac hypertrophy, it is necessary to characterize the effect of GCIP-27 on vascular remodeling. Therefore the present study was designed to explore the potential effects of GCIP-27 on proliferation of VSMC and vascular remodeling in spontaneously hypertensive rats (SHR). MATERIALS AND METHODS AnimalsMale SHR and Wi...

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

“…Several studies have demonstrated a beneficial effect of the GCIP-27 polypeptide on cardiac hypertrophy induced by a variety of factors in vivo and in vitro [ 15 – 19 ]. Cardiac hypertrophy is an important factor in the development of CHF.…”

“…And due to compensation, the normotensive animals, such as rats, dogs and patients, are less sensitive to hypotensive agents, such as losartan and nitroprusside, etc., than hypertensive subjects [ 32 , 33 ]. We have also ever observed that GCIP-27 had no influence on the blood pressure in normotensive rats [ 17 , 19 ]. In doxorubicin-induced heart failure rats, blood pressure and hemodynamic parameters showed a slight decrease or no change [ 34 , 35 ].…”

“…Gαq protein carboxyl terminus imitation polypeptide (GCIP)-27 is a synthetic polypeptide that was previously designed and optimized in our laboratory [ 15 ]. Serial studies indicated that the GCIP-27 peptide could be preferentially transported into cardiomyocytes and vascular smooth muscle cells through an energy-dependent endocytosis mechanism [ 16 ], inhibiting cardiomyocyte hypertrophy induced by angiotensin II or norepinephrine in vitro and alleviating left ventricular hypertrophy in various animal models [ 15 – 19 ]. Based on these results, there is little doubt that GCIP-27 could ameliorate CHF by alleviating cardiac hypertrophy.…”