Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation

Increased abundance of GRK2 [G protein–coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In addition to its role in down-regulating activated GPCRs, GRK2 also localizes to mitochondria both basally and post-IR injury, where it regulates cellular metabolism. We previously showed that phosphorylation of GRK2 at Ser670 is essential for the translocation of GRK2 to the mitochondria of cardiomyocytes post-IR injury in vitro and that this localization promotes cell death. Here, we showed that mice with a S670A knock-in mutation in endogenous GRK2 showed reduced cardiomyocyte death and better cardiac function post-IR injury. Cultured GRK2-S670A knock-in cardiomyocytes subjected to IR in vitro showed enhanced glucose-mediated mitochondrial respiratory function that was partially due to maintenance of pyruvate dehydrogenase activity and improved glucose oxidation. Thus, we propose that mitochondrial GRK2 plays a detrimental role in cardiac glucose oxidation post-injury.
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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An increasing amount of evidence reveals that the gut microbiota is involved in the pathogenesis and progression of various cardiovascular diseases. In patients with heart failure (HF), splanchnic hypoperfusion causes ischemia and intestinal edema, allowing bacterial translocation and bacterial metabolites to enter the blood circulation via an impaired intestinal barrier. This results in local and systemic inflammatory responses. Gut microbe-derived metabolites are implicated in the pathology of multiple diseases, including HF.
Source: Translational Research - Category: Research Authors: Tags: Review Article Source Type: research
In conclusion, decrease of [Cl-]i suppresses angiogenesis via inhibiting oxidase stress-mediated VEGFR2 signaling activation by preventing NADPH oxidase complex formation and promoting VEGFR2/PTP1B association, suggesting that modulation of [Cl-]i may be a novel therapeutic avenue for the treatment of angiogenic dysfunction-associated diseases. PMID: 32694758 [PubMed - as supplied by publisher]
Source: Acta Pharmacologica Sinica - Category: Drugs & Pharmacology Authors: Tags: Acta Pharmacol Sin Source Type: research
This study aimed to clarify the regional modulatory effect of Qiliqiangxin capsules (QLQX), a traditional Chinese medicine, on cardiac metabolic phenotypes. Sprague–Dawley rats underwent left anterior descending coronary artery ligation and were treated with QLQX and enalapril. Striking global left ventricular dysfunction and left ventricular remodeling were significantly improved by QLQX. In addition to the posterior wall, QLQX also had a unique beneficial effect on the anterior wall subject to a severe oxygen deficit. Cardiac tissues in the border and remote areas were separated for detection. QLQX enhanced the car...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Dilated Cardiomyopathy Mutations in Thin Filament Regulatory Proteins Reduce Contractility, Suppress Systolic Ca2+ &Activate NFAT &AKT Signalling. Am J Physiol Heart Circ Physiol. 2020 Jul 03;: Authors: Robinson P, Sparrow AJ, Patel S, Malinowska M, Reilly SN, Zhang YH, Casadei B, Watkins H, Redwood C Abstract Dilated cardiomyopathy (DCM) is clinically characterised by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk. Mutations in thin filament regulatory proteins can cause DCM and have been shown in vitro to reduce contract...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Tags: Am J Physiol Heart Circ Physiol Source Type: research
Anti-inflammatory effects of higenamine (Hig) on LPS-activated mouse microglia (BV2) through NF-κB and Nrf2/HO-1 signaling pathways. Int Immunopharmacol. 2020 Jun 11;85:106629 Authors: Yang S, Chu S, Ai Q, Zhang Z, Gao Y, Lin M, Liu Y, Hu Y, Li X, Peng Y, Pan Y, He Q, Chen N Abstract Microglia are the most widely equipped protective cells in the brain and play a pivotal role in the development of neurological diseases. Inflammatory response and oxidative stress are critical risk factors in the activation of microglia which may cause various neurological diseases. Higenamine (Hig), a plant-based ...
Source: International Immunopharmacology - Category: Allergy & Immunology Authors: Tags: Int Immunopharmacol Source Type: research
ConclusionOur data show that sGC activator improves cardiomyocyte function, reduces inflammation and oxidative stress, improves sGC–PKG signaling, and normalizes hypertrophic kinases, indicating that it is a potential treatment option for HFpEF patients and perhaps also for cases with increased hypertrophic signaling.
Source: Frontiers in Physiology - Category: Physiology Source Type: research
In conclusion, our study demonstrated that Nrf2 deficiency promoted the increasing trend of autophagy during aging in skeletal muscle. Nrf2 deficiency and increasing age may cause excessive autophagy in skeletal muscle, which can be a potential mechanism for the development of sarcopenia. To What Degree is Chondrocyte Hypertrophy in Osteoarthritis Due to Cellular Senescence? Senescent cells are large. They do not replicate, that function is disabled, but it is as if they go ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study we evaluated the beneficial effects of cardamonin (CAR), a flavone existing in Alpinia plant, on endotoxemia-induced cardiac dysfunction and the underlying mechanisms with focus on oxidative stress and apoptosis. Adult mice were exposed to LPS (4 mg/kg, i.p. for 6 h) prior to functional or biochemical assessments. CAR (20 mg/kg, p.o.) was administered to mice immediately prior to LPS challenge. We found that LPS challenge compromised cardiac contractile function, evidenced by compromised fractional shortening, peak shortening, maximal velocity of shortening/relengthening, enlarged LV end ...
Source: Acta Pharmacologica Sinica - Category: Drugs & Pharmacology Authors: Tags: Acta Pharmacol Sin Source Type: research
Authors: Sun B, Meng M, Wei J, Wang S Abstract Long noncoding RNAs (lncRNAs) and microRNAs (miRs) serve critical roles in various cellular processes and can be used as noninvasive biomarkers in human diseases. The present study aimed to investigate the effects of lncRNA plasmacytoma variant translocation 1 (PVT1) and miR-190a-5p on vascular endothelial cell (EC) proliferation and assess their clinical value in the diagnosis of chronic heart failure (CHF). The expression of PVT1 and miR-190a-5p was investigated using reverse transcription-quantitative PCR. The interaction between PVT1 and miR-190a-5p was confirmed u...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
Conclusions/interpretationOur study provides the first evidence thatAkap1 deficiency exacerbates diabetic cardiomyopathy by impeding mitochondrial translocation of NDUFS1 to induce mitochondrial dysfunction and cardiomyocyte apoptosis. Our findings suggest thatAkap1 upregulation has therapeutic potential for myocardial injury in individuals with diabetes.
Source: Diabetologia - Category: Endocrinology Source Type: research
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