A new, potent poly(ADP-ribose) polymerase inhibitor improves cardiac and vascular dysfunction associated with advanced aging

Abstract

Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension, and aging. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury, circulatory shock, and aging. Here, we investigated the effect of a new PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction associated with advanced aging using Millar's new Aria pressure-volume conductance system and isolated aortic rings. Young adult (3 months old) and aging (24 months old) Fischer rats were treated for 2 months with vehicle, or the potent PARP inhibitor INO-1001. In the vehicle-treated aging animals, there was a marked reduction of both systolic and diastolic cardiac function and loss of endothelial relaxant responsiveness of aortic rings to acetylcholine. Treatment with INO-1001 improved cardiac performance in aging animals and also acetylcholine-induced, nitric oxide-mediated vascular relaxation. Thus, pharmacological inhibition of PARP may represent a novel approach to improve cardiac and vascular dysfunction associated with aging.

Fig. 1

Pharmacological inhibition of PARP (for 2 months) does not affect the cardiac remodeling and lung edema associated with advanced aging. Left ventricular (LVW), right ventricular (RVW), atrial (AW) and lung (LungW) weights in young adult (Y), young adult treated with INO-1001 (Y+INO), aging (A), and aging treated with INO-1001 (A+INO) male Fischer rats were normalized to body weight (BW). Values are mean ± S.E.M. of 6 to 10 experiments in each group. *, P < 0.05 versus young adult controls.

Fig. 2

Representative PV loops (top part) and left ventricular pressure signal (bottom part) from young adult, aging, and aging treated with INO-1001 rats. Please note that the rightward shift of PV loops in aging animals, the decrease of maximal left ventricular pressure, and +dP/dt indicate depressed cardiac contractility and heart failure. INO-1001 moderately improves baseline contractile function.

Fig. 3

Pharmacological inhibition of PARP (for 2 months) improves cardiac dysfunction associated with advanced aging. Mean blood pressure (mean BP), LVSP, LVEDP, heart rate, +dP/dt and -dP/dt, EF, time constant of left ventricular pressure decay, stroke volume, SWI, CI, and TPRI in young adult (Y), young adult treated with INO-1001 (Y+INO), aging (A), and aging treated with INO-1001 (A+INO) male Fischer rats. Values are mean ± S.E.M. of 6 to 10 experiments in each group. *, P < 0.05 versus young controls; #, P < 0.05 versus aging.

Fig. 4

Pharmacological inhibition of PARP (for 2 months) improves ESPVR and EDPVR in advanced aging-associated heart failure. Representative PV loops obtained with PV conductance catheter system at different preloads, showing difference in ESPVR and EDPVR between young adult (Y), aging (A), and aging treated with INO-1001 (A+INO-1001) rats. The less steep ESPVR in aging animals (middle panel) compared with control young adult rats (upper panel) indicates severely decreased contractile function in aging, which is improved by INO-1001 treatment (lower panel). The steeper EDPVR in aging rats indicates increased end-diastolic stiffness, which is also improved by INO-1001 treatment.

Fig. 5

Pharmacological inhibition of PARP (for 2 months) improves ESPVR (E_max), PRSW, +dP/dt-EDV, EDPVR, and efficiency in advanced aging-associated heart failure. Overall values of E_max, PRSW, dP/dt-EDV, EDPV relationships, and efficiency. Values as mean ± S.E.M. of 6 to 10 experiments in each group. *, P < 0.05 versus young adult; #, P < 0.05 versus aging.

Fig. 6

Improvement of advanced aging-induced endothelial dysfunction by pharmacological inhibition of PARP in rats. Acetylcholine-induced endothelium-dependent relaxation. Each point of the curve represent mean ± S.E.M. of 7 to 10 experiments in vascular rings. *, P < 0.05 versus young adult; #, P < 0.05 versus aging.