Impaired Activity of Ryanodine Receptors Contributes to Calcium Mishandling in Cardiomyocytes of Metabolic Syndrome Rats

Abstract

Metabolic syndrome (MetS) has become a global epidemic. MetS is a serious health problem because of its related cardiovascular complications, which include hypertension and delayed heart rate recovery after exercise. The molecular bases of cardiac dysfunction in MetS are still under scrutiny and may be related to anomalies in the activity and expression of key proteins involved in the cardiac excitation–contraction coupling (ECC). The cardiac Ca 2+ channel/ryanodine receptor (RyR2) participates in releasing Ca 2+ from internal stores and plays a key role in the modulation of ECC. We examined alterations in expression, phosphorylation status, Ca 2+ sensitivity, and in situ function (by measuring Ca 2+ sparks and Ca 2+ transients) of RyR2; alterations in these characteristics could help to explain the Ca 2+ handling disturbances in MetS cardiomyocytes. MetS was induced in rats by adding commercially refined sugar (30% sucrose) to their drinking water for 24 weeks. Cardiomyocytes of MetS rats displayed decreased Ca 2+ transient amplitude and cell contractility at all stimulation frequencies. Quiescent MetS cardiomyocytes showed a decrease in Ca 2+ spark frequency, amplitude, and spark-mediated Ca 2+ leak. The [ 3 H]-ryanodine binding data showed that functionally active RyRs are significantly diminished in MetS heart microsomes; and exhibited rapid Ca 2+ -induced inactivation. The phosphorylation of corresponding Ser2814 (a preferential target for CaMKII) of the hRyR2 was significantly diminished. RyR2 protein expression and Ser2808 phosphorylation level were both unchanged. Further, we demonstrated that cardiomyocyte Ca 2+ mishandling was associated with reduced SERCA pump activity due to decreased Thr17-PLN phosphorylation, suggesting a downregulation of CaMKII in MetS hearts, though the SR Ca 2+ load remained unchanged. The reduction in the phosphorylation level of RyR2 at Ser2814 decreases RyR2 availability for activation during ECC. In conclusion, the impaired in situ activity of RyR2 may also account for the poor overall cardiac outcome reported in MetS patients; hence, the SERCA pump and RyR2 are both attractive potential targets for future therapies.

FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

“…With respect to ER Ca 2+ regulatory machineries, cardiac up-regulation of IP3R3 and IP3R2 receptors, down-regulation of SERCA2a, and decreased RyR2 activity (T2814 phosphorylation) caused by HF feeding were noted in HF diet–fed mouse hearts and are responsible for feeding Ca 2+ from the ER to mitochondria, resequestration of Ca 2+ into ER, and releasing Ca 2+ from ER/sarcoplasmic reticulum stores, respectively ( 32 ). Consistent with our present findings, earlier work demonstrated decreased cardiac SERCA levels and RyR2 Ca 2+ release as well as elevated hepatic IP3R1 and IP3R2 in metabolic diseases including diet-induced obesity ( 33 , 34 ). The disparity in IP3Rs subtypes may be related to tissue specificity.…”

Metabolic syndrome diminishes insulin-induced Akt activation and causes a redistribution of Akt-interacting proteins in cardiomyocytes

“…Those results are in agreement with our model of sucrose supplementation in drinking water, in which the rats became obese with an increased epididymal fat and body weight (Table 1) [25]. The weight gain in our model [25] contrasts with other studies using the same animal model in which no weight differences [45][46][47] or much lower weight increases were found [48]. Regardless of the variability in the characteristics developed, sucrose-induced MetS has been a frequently studied model to elucidate molecular alterations of this condition [45][46][47][48][49], and the sucrose-drinking protocol used in our study induced central characteristics of MetS, such as obesity, hyperinsulinemia, hypertriglyceridemia, and insulin resistance ( Table 1 and Fig 1).…”

“…About the sucrose delivery mode, Singh et al [43] reported that male Sprague Dawley rats fed with high sucrose diet (55% of energy as sucrose) supplied by pellets for 15 weeks, did not develop obesity, hypertriglyceridemia or insulin resistance, unlike reported in other studies [44], however, by supplying sucrose in the drinking water (32% sucrose), rats developed obesity and insulin resistance in 8 to 10 weeks [43]. Those results are in agreement with our model of sucrose supplementation in drinking water, in which the rats became obese with an increased epididymal fat and body weight (Table 1) [25]. The weight gain in our model [25] contrasts with other studies using the same animal model in which no weight differences [45][46][47] or much lower weight increases were found [48].…”

“…The Institutional Bioethical Committee approved it for Care and Handling of Laboratory Animals at the Cinvestav-IPN (approved CICUAL protocol No. 0105-14) [25].…”

Gender Differences in the Pharmacological Actions of Pegylated Glucagon-Like Peptide-1 on Endothelial Progenitor Cells and Angiogenic Precursor Cells in a Combination of Metabolic Disorders and Lung Emphysema

“…All the results were expressed as mmol/l. On p189, TG/HDL was assessed, as previously described in [49,50].…”