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

Laszlo Deres,Balazs Sumegi,Robert Halmosi,Adam Riba,Kalman Hideg,Kalman Toth,Janos Lantos,Eva Bartha,Anita Palfi,Krisztian Eros,Ferenc Gallyas,Tamas Kalai,Rajesh Gopalrao Katare

doi:10.1371/journal.pone.0102148

Laszlo Deres, Balazs Sumegi + Show 11 more

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https://doi.org/10.1371/journal.pone.0102148

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Journal: PloS one	Publication Date: Jul 11, 2014
Citations: 58	License type: CC BY 4.0

Affiliation: University of Pecs

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-1Ser473, glycogen synthase kinase (GSK)-3βSer9, 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)1/2Thr183-Tyr185, Akt-1Ser473, GSK-3βSer9, FKHRSer256, and PKC εSer729 and the level of Hsp90 were increased, while the activity of PKC α/βIIThr638/641, ζ/λ410/403 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.

Highlights

Left ventricular hypertrophy (LVH) represents the heart’s response to increased biomechanical stress such as arterial hypertension or valvular heart disease
WKY: normotensive age-matched control rats, n = 7, Spontaneously hypertensive rat (SHR)-C: SHR age-matched control rats, n = 8, SHR-L: n = 9, SHR treated with L-2286 for 24 weeks.EF6w: ejection fraction, FS6w: fractional shortening, LVEDV6w: left ventricular (LV) end-diastolic volume, LVESV6w: LV end-systolic volume, Septum6w: thickness of septum, PW6w: thickness of posterior wall, LV mass6w: weights of LVs
WKY: normotensive age-matched control rats, n = 7, SHR-C: SHR age-matched control rats, n = 8, SHR-L: n = 9, SHR treated with L-2286 for 24 weeks.EF30w: ejection fraction, F30w: fractional shortening, LVEDV30w: left ventricular (LV) end-diastolic volume, LVESV30w: LV end-systolic volume, Septum30w: thickness of septum, PW30w: thickness of posterior wall, RWT30w: relative wall thickness, LV mass30w: weights of LVs

Summary

Introduction

Left ventricular hypertrophy (LVH) represents the heart’s response to increased biomechanical stress such as arterial hypertension or valvular heart disease. Recent clinical studies as well as several animal models have shown that cardiac hypertrophy is rather a maladaptive process, leading to heart failure (HF) and sudden cardiac death independent of the underlying cause of hypertrophy [1] Both physiologic and pathologic stimulation-induced cellular adaptations of the heart are typically initiated by stress-responsive signaling pathways, which serve as central transducers of cardiac hypertrophic growth and/or ventricular dilation. These signaling pathways include extracellular signal-regulated protein kinases (ERK), p38 mitogen-activated protein kinases (p38-MAPK), c-Jun NH2-terminal kinases (JNK) and several protein kinase C (PKC) isoforms [2]. These pathways and the Akt-1/glycogen synthase kinase-3b (GSK-3b) signaling cascade have all been demonstrated to alter their activation state in response to hypertrophic stimuli, and may contribute to myocardial remodeling [3]

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