Abstract 3938: Oxidative Stress, Mitochondrial Permeability Pore Opening and Cardiac Hypertrophy With Fibrosis in Aldosteronism: Response to Supplemental Zinc
Background. Aldosterone/salt treatment (ALDOST) leads to intracellular Ca2+ overloading and the induction of oxidative stress in cardiomyocytes and mitochondria with an opening of the mitochondrial permeability pore (mPTP) to eventuate in necrotic cell death with subsequent scarring. Concomitant are reduced antioxidant defenses promoted by excretory Zn2+ losses. We hypothesized a Zn2+ supplement would ameliorate the prooxidant:antioxidant imbalance and prove cardioprotective.
Methods. Eight-wk-old uninephrectomized rats received 4 wk ALDOST alone or with ZnSO4 cotreatment (40 mg/day; gavage) were compared to unoperated/untreated age-/sex-matched controls (n=6/group). We monitored: arterial pressure by tail cuff plethysmography; echocardiographic ventricular function; fibrosis by histochemistry; cardiomyocyte size by planimetry and biomarkers of hypertrophy, including myosin heavy-chain (MHC-α and -β) and pro-atrial natriuretic peptide (ANP) mRNAs; oxidative stress by tissue 8-isoprostane, glutathione peroxidase (GSH-Px) activity and mitochondrial H2O2 production; mPTP opening with Ca2+-induced swelling of isolated mitochondria; and endoplasmic reticulum (ER) stress by BiP/GRP78 and protein disulfide isomerase (PDI) using real-time PCR and immunoblotting.
Results. Compared to ALDOST alone, ZnSO4 cotreatment: attenuated scarring and the rise in interstitial collagen volume fraction (4.79±0.87 and 3.89±0.34%, respectively, vs. controls 2.22±0.04%); increased (p<0.05) fractional shortening (53±2 and 42±5% vs. controls 46±2%), without preventing hypertension or hypertrophy; reduced (p<0.05) atrophy and oxidative stress, including mitochondrial H2O2 production and ER stress while preventing mPTP opening.
Conclusion. In the hypertrophy that accompanies aldosteronism, the induction of oxidative stress, coupled with mPTP opening, ER stress and reduced antioxidant defenses, contribute to cardiomyocyte necrosis and scarring with reduced ventricular function. This can be overcome by fortifying the heart’s antioxidant capacity with a Zn2+ supplement.