Abstract 4833: Protective Effect of a Quinazoline-Type Poly(ADP-Ribose)Polymerase Inhibitor Against the Development of Hypertensive Cardiomyopathy and Heart Failure
Purpose: Spontaneously hypertensive rat (SHR) is a suitable model for studies of hypertension and consequential left ventricular (LV) hypertrophy and heart failure. It is known, that activation of poly(ADP-ribose)polymerase enzyme (PARP) plays a role in the development of postinfarction myocardial remodeling. In our work we examined the effect of a PARP inhibitor (L-2286) against the development of hypertensive cardiopathy and heart failure in SHRs.
Methods: Male 6-week-old SHR rats were treated with L-2286 (n=32, SHR-L) or placebo (n=32, SHR-C) for 50 weeks. Male CFY rats were used as aged-matched, normotensive controls (n=7, CFY). The phosphorylation state of signal transduction proteins were monitored by Western blotting. To detect the extent of fibrosis, histologic samples were stained with Masson’s trichrome. Plasma BNP activity was also determined. Before the study, after 24 weeks, and at the end of the treatment period echocardiography was performed.
Results: L-2286 treatment enhanced the phosphorylation of the prosurvival factors Akt-1/GSK-3β and PKC ϵ (p<0.01), while phosphorylation of JNK, p-38 MAPK, PKC pan (p<0.01), PKC α/β, δ (p<0.05) were significantly ameliorated in SHR-L group. Interstitial collagen accumulation and plasma BNP activity were significantly elevated (p<0.05) in SHR-L and SHR-C groups compared to the CFY group. These parameters were improved due to L-2286 treatment (p<0.01 and p<0.05, respectively). Echocardiography showed that the measured parameters did not differ significantly among the three groups at baseline. After 24 weeks, LV end-diastolic and end-systolic volumes and LV wall thickness increased (p<0.05 SHR-L and SHR-C vs. CFY). All these parameters decreased by L-2286 treatment (p<0.05 SHR-L vs. SHR-C). At the end of the study in SHR-L group LV hypertrophy with preserved LV ejection fraction, however in the SHR-C group an excentric hypertrophy with poor systolic function was observable. As a hard endpoint, the survival rate was significantly better in SHR-L group (p<0.05) compared to SHR-C group.
Conclusions: We demonstrated that PARP inhibition has a beneficial effect against the development of LV hypertrophy and heart failure in SHRs, due to the activation of PKC ϵ, and Akt-1/GSK-3β signaling pathways.