Abstract 51: Aldosterone Induces Cardiac Deleterious Effects Through A Grk2 And Grk5 Dependent Pathway
High Aldosterone (Aldo) plasma levels are present in heart failure patients and are associated with increased cardiac fibrosis and hypertrophy. These effects have been shown to be, in part, related to the transactivation of the angiotensin II receptor (AT1R), a G-protein coupled receptor (GPCR). In this regard, the GPCR kinase 2 (GRK2) and 5 (GRK5) are both critical regulators of cardiac function through GPCR regulation. Since these GRKs have also been shown to play a role in cardiac hypertrophy and HF development we investigated whether these kinases may play a role in myocardial Aldo signaling. To test this, we first treated neonatal rat ventricular cardiomyocytes (NRVMs) with Aldo (1 μM) and looked for GRK regulation. Following 12 hrs of Aldo-stimulation we observed a significant increase in both GRK2 and GRK5 protein levels. We also found that Aldo induced the localization of GRK2 to mitochondria, which the lab has previously found to occur following ischemic injury leading to increased cell death and mitochondrial dysfuntion. Indeed, high Aldo on NRVMs led to a significant increase in ROS generation and cell death, as observed by Mitosox Red and TUNEL staining, respectively. Notably, all these effects were abolished respectively by Spironolactone (Spiro, an Aldo receptor blocker) or Losartan (Los, an AT1R antagonist) pre-treatment. Next, in nuclear fractions, purified from Aldo-treated NRVMs, we observed a consistent increase in GRK5 nuclear localization that consequently induced a significant activation of hypertrophic genes, which is consistent with previous studies showing GRK5 being a key regulator of maladaptive cardiac hypertrophy after pressure-overload. Importantly, Spiro pre-treatment efficiently abolished these effects of GRK5. Finally, we treated wild-type mice in vivo with Aldo for two and four weeks and not only found that this induced significant cardiac hypertrophy and fibrosis compared to saline-treated mice, we also found significant increases in levels of GRK2 and GRK5. Therefore, our study provide, for the first time, data demonstrating that GRK2 and GRK5 are potential regulators of Aldo-mediated cardiac pathology acting either down-stream of mineralocorticoid receptor or transactivated AT1Rs.
Author Disclosures: A. Cannavo: None D. Liccardo: None S.M. Bass: None B. Woodall: None C.J. Traynham: None J. Ibetti: None G. Rengo: None W.J. Koch: None.
- © 2014 by American Heart Association, Inc.