PP242, mTOR inhibitor, decreases phenylephrine‐induced vascular contractility in hypertensive and normotensive arteries

Abstract

Cardiovascular disease is the leading cause of death in cancer survivors. The short‐term and long‐term cardiotoxic effects of targeted chemotherapeutics is not well known. PP242, a dual inhibitor to mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and 2 (mTORC2), is a targeted therapy in clinical trials for various malignancies including bladder, ovarian and gastric cancer. mTORC1 inhibition has been associated with heart failure, while mTORC2 inhibition has been considered cardioprotective. We hypothesized that PP242 leads to enhancedcontractile response to phenylephrine (PE), and impaired Acetylcholine (ACh)‐induced relaxation. We studied the effects of PP242 on the contractility and relaxation of aortic rings and mesenteric resistance arteries (MRA) of male Wistar rats (12–15 weeks old, n=4) and spontaneously hypertensive rats (SHR) (15–18 weeks old, n=6) on a wire myograph. Vessel segments were exposed to PP242 (500nM) for one‐hour incubation. Normotensive aortic rings exposed to PP242 showed a decreased contractile response to PE (LogEC50±SEM, Ctrl:−7.617±0.178 vs Drug: −7.292±0.129) and increased relaxation to ACh (LogEC50±SEM, Ctrl:−6.917±0.164 vs Drug: −7.588±0.164). SHR aortic rings exposed to PP242 (LogEC50±SEM, Ctrl:−7.606±0.129 vs Drug: −7.124±0.118) showed decreased contractility but no difference in ACh‐induced relaxation. No differences were observed in normotensive MRA. SHR MRA showed decreased PE‐induced contraction (LogEC50±SEM, Ctrl:−5.402±0.060 vs Drug:‐−5.322±0.065) and increased ACh‐induced relaxation (LogEC50±SEM, Ctrl:−7.992±0.117 vs Drug:−8.139±0.092). Our data suggest that dual inhibition of mTORC1 and mTORC2 with PP242 may provide a cardioprotective effect by limiting vasoconstriction and may be a good therapeutic agent for hypertensive cancer patients. However, long term treatments with this targeted therapy need to be evaluated for vascular dysfunction induction, as the hypocontractile effect could contribute to failure of the cardiovascular system, which could be associated with cardiotoxicity.Support or Funding InformationNIH P01 HL134604 (RCW), k99GM11888 (CFW)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.