Role of G Protein-Coupled Receptor Kinase-2 in Peroxisome Proliferator-Activated Receptor Gamma-Mediated Modulation of Blood Pressure and Renal Vascular Reactivity in SHR

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear transcription factor, modulates the expression/activity of G protein-coupled receptors (GPCRs), but its role in GPCR signaling is not clear. Increased GPCR kinase-2 (GRK-2) activity and receptor desensitization have been reported in hypertension. METHOD: In this study we investigated the role of GRK-2 in PPARγ-mediated blood pressure regulation in hypertension. SHR or WKY rats were treated with GW1929, a selective PPARγ ligand (0.5 mg/kg/day), or vehicle for 2 months. Systolic blood pressure (tail cuff plethysmography), whole kidney perfusion (laser scanner) and renal vascular reactivity (isolated perfused kidney) was determined. RESULTS: GW1929 significantly reduced blood pressure (20 ± 1%) and increased renal perfusion (61 ± 3%) in SHR compared to WKY rats. Vasoconstriction to phenylephrine (100 μg) in the isolated perfused kidney was greater in SHRs (29 ± 1%) compared to WKY rats and this was abolished by GW1929. GW1929 enhanced acetylcholine-induced (30–300 μg) and sodium nitroprusside-induced vasodilatation in SHR by 46 ± 2% (p < 0.05) and 33 ± 2% (p < 0.05), respectively. Isoprenalin-induced (5–30 μg) vasodilatation was 43 ± 2% lower in SHR compared to WKY and GW1929 enhanced this vasodilatation by 55 ± 2%. In SHR kidney, GW1929 enhanced expression of PPARγ mRNA (34 ± 1%) but reduced that of GRK-2 (31 ± 3%). CONCLUSION: We suggest that downregulation of PPARγ but upregulation of GRK-2 increases blood pressure and impaired renal vascular reactivity in SHR and that PPARγ-mediated improvement in hypertension may involve transcriptional regulation of GRK-2 function

Histone deacetylase inhibitors as multitarget-directed epi-drugs in blocking pi3k oncogenic signaling: A polypharmacology approach

Genetic mutations and aberrant epigenetic alterations are the triggers for carcinogenesis. The emergence of the drugs targeting epigenetic aberrations has provided a better outlook for cancer treatment. Histone deacetylases (HDACs) are epigenetic modifiers playing critical roles in numerous key biological functions. Inappropriate expression of HDACs and dysregulation of PI3K signaling pathway are common aberrations observed in human diseases, particularly in cancers. Histone deacetylase inhibitors (HDACIs) are a class of epigenetic small-molecular therapeutics exhibiting promising applications in the treatment of hematological and solid malignancies, and in non-neoplastic diseases. Although HDACIs as single agents exhibit synergy by inhibiting HDAC and the PI3K pathway, resistance to HDACIs is frequently encountered due to activation of compensatory survival pathway. Targeted simultaneous inhibition of both HDACs and PI3Ks with their respective inhibitors in combination displayed synergistic therapeutic efficacy and encouraged the development of a single HDAC-PI3K hybrid molecule via polypharmacology strategy. This review provides an overview of HDACs and the evolution of HDACs-based epigenetic therapeutic approaches targeting the PI3K pathway

Contribution of PPAR gamma in modulation of acrolein-induced inflammatory signaling in gp91phox knock-out mice

Oxidative stress and inflammation are major contributors in acrolein toxicity. Peroxisome Proliferator Activated Receptor gamma (PPARγ) has antioxidant/anti-inflammatory effects. We investigated contribution of PPARγ ligand, GW1929, in attenuation of oxidative stress in acrolein-induced insult. Male gp91phox knockout (KO) mice were treated with acrolein (0.5 mg/kg; i.p.7 days) with/without GW1929 (GW, 0.5 mg/kg/day; orally-10 days). Liver was processed for further analysis. Acrolein significantly increased 8-Isoprostane and reduced PPARγ activity (PThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Cellular effects of butyrate on vascular smooth muscle cells are mediated through disparate actions on dual targets, histone deacetylase (HDAC) activity and Pi3k/Akt signaling network

Vascular remodeling is a characteristic feature of cardiovascular diseases. Altered cellular processes of vascular smooth muscle cells (VSMCs) is a crucial component in vascular remodeling. Histone deacetylase inhibitor (HDACI), butyrate, arrests VSMC proliferation and promotes cell growth. The objective of the study is to determine the mechanism of butyrate-induced VSMC growth. Using proliferating VSMCs exposed to 5 mM butyrate, immunoblotting studies are performed to determine whether PI3K/Akt pathway that regulates different cellular effects is a target of butyrate-induced VSMC growth. Butyrate inhibits phosphorylation-dependent activation of PI3K, PDK1, and Akt, eliciting differential effects on downstream targets of Akt. Along with previously reported Ser9 phosphorylation-mediated GSK3 inactivation leading to stability, increased expression and accumulation of cyclin D1, and epigenetic histone modifications, inactivation of Akt by butyrate results in: transcriptional activation of FOXO1 and FOXO3 promoting G1 arrest through p21Cip1/Waf1 and p15INK4B upregulation; inactivation of mTOR inhibiting activation of its targets p70S6K and 4E-BP1 impeding protein synthesis; inhibition of caspase 3 cleavage and downregulation of PARP preventing apoptosis. Our findings imply butyrate abrogates Akt activation, causing differential effects on Akt targets promoting convergence of cross-talk between their complimentary actions leading to VSMC growth by arresting proliferation and inhibiting apoptosis through its effect on dual targets, HDAC activity and PI3K/Akt pathway network