PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/GSK-3β and several PKC isoforms.

Abstract

Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1(Ser473), glycogen synthase kinase (GSK)-3β(Ser9), forkhead transcription factor (FKHR)(Ser256), mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2(Thr183-Tyr185), Akt-1(Ser473), GSK-3β(Ser9), FKHR(Ser256), and PKC ε(Ser729) and the level of Hsp90 were increased, while the activity of PKC α/βII(Thr638/641), ζ/λ(410/403) were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling.

• Authors: Laszlo Deres, Eva Bartha, Anita Palfi, Krisztian Eros, Adam Riba, Janos Lantos, Tamas Kalai, Kalman Hideg, Balazs Sumegi, Ferenc Gallyas, Kalman Toth, Robert Halmosi
• Journal: PloS one (PLoS One) Vol. 9 Issue 7 Pg. e102148 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25014216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one
• Forkhead Transcription Factors
• HSP90 Heat-Shock Proteins
• Isoenzymes
• Nerve Tissue Proteins
• Piperidines
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinazolines
• Natriuretic Peptide, Brain
• Foxo1 protein, rat
• Poly(ADP-ribose) Polymerases
• Akt1 protein, rat
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Protein Kinase C
• Extracellular Signal-Regulated MAP Kinases
• Glycogen Synthase Kinase 3

Topics

• Animals
• Blood Pressure (drug effects)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• HSP90 Heat-Shock Proteins (genetics, metabolism)
• Heart Failure (etiology, genetics, physiopathology, prevention & control)
• Hypertension (complications, drug therapy, genetics, physiopathology)
• Hypertrophy, Left Ventricular (drug therapy, etiology, genetics, physiopathology)
• Isoenzymes (genetics, metabolism)
• Male
• Natriuretic Peptide, Brain (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Phosphorylation
• Piperidines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Protein Kinase C (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Quinazolines (pharmacology)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Signal Transduction