Impact of oxidative posttranslational modifications of SERCA2 on heart failure exacerbation in young patients with non-ischemic cardiomyopathy: A pilot study

Abstract

BackgroundOxidative posttranslational modifications (OPTM) impair the function of Sarcoplasmic/endoplasmic reticulum (SR) calcium (Ca2+) ATPase (SERCA) 2 and trigger cytosolic Ca2+ dysregulation. We investigated the extent of OPTM of SERCA2 in patients with non-ischemic cardiomyopathy (NICM).Methods and resultsEndomyocardial biopsy (EMB) was obtained in 40 consecutive patients with NICM. Total expression and OPTM of SERCA2, including sulfonylation at cysteine-674 (S-SERCA2) and nitration at tyrosine-294/295 (N-SERCA2), were examined by immunohistochemical analysis. S-SERCA2 increased in the presence of late gadolinium enhancement on cardiac magnetic resonance imaging. S-SERCA2/SERCA2 and N-SERCA2/SERCA2 correlated with cardiac fibrosis evaluated by Masson’s trichrome staining of EMB. SERCA2 expression modestly increased in parallel with an upward trend in OPTM of SERCA2 with aging. This tendency became prominent only in patients aged >65 years. OPTM of SERCA2 positively correlated with brain natriuretic peptide (BNP) values only in patients aged ≤65 years. Composite major adverse cardiac events (MACE) increased more in the high OPTM group of younger patients; however, MACE-free survival was similar irrespective of the extent of OPTM in older patients.ConclusionsOPTM of SERCA2 correlate with myocardial fibrosis in NICM. In younger patients, OPTM of SERCA2 correlate with elevated BNP and increased composite MACE.

SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways

“…SERCA2 is the only known molecular pump mediating calcium reuptake and is thus critically responsible for buffering intracellular calcium transients 51 . Oxidation of SERCA2 promotes its inactivation, a phenomenon that contributes to cardiomyocyte stiffness during heart failure 24 , 25 . Western blotting (Figure 4 F-H) showed that H/R promoted SERCA2 oxidation at Cys-674, an effect that was accompanied with a drop in SERCA activity (Figure 4 I).…”

“…Sarco(endo)plasmic reticulum Ca 2+ -ATPase-2 (SERCA2) is the primary mechanism for Ca 2+ uptake into the SR/ER 20 , 21 . SERCA2 oxidation at Cys-674 promotes SERCA2 degradation and thus increases baseline intracellular calcium levels 22 , 23 , a pivotal phenomenon in myocardial dysfunction during heart failure 24 , 25 . Moreover, decreased SERCA2 expression has been found to contribute to IRI-related microvascular damage 14 , 26 - 28 .…”

Type 1 Diabetes Impairs Cardiomyocyte Contractility in the Left and Right Ventricular Free Walls but Preserves It in the Interventricular Septum

“…The functional abnormalities in ventricular CM that we observed can relate to T1Dinduced oxidative stress and glycosylation, which can directly affect CM contractility by modifying sarcomeric proteins [59] or impact Ca 2+ -handling proteins [60].…”

Biomarkers of Oxidative Stress Tethered to Cardiovascular Diseases

“…Modified natural LDL components such as apoβ, a surface protein of LDL, improve the ability of LDL to attach to its receptor [24]. In contractile failure, the contractility is altered by the oxidation of Sarco and endoplasmic Ca+2-ATPase as well as contractile proteins, including tropomyosin and actin [25,26]. The impact of ROS on endothelium underpinning molecules that can induce death, inflammation, and therefore clotting plaque formation in atherosclerosis makes oxidative stress a critical characteristic of CVD, which is also characterized as an initial causal component [27,28].…”