Contribution of TRPV4 to enhanced calcium cycling and cardiac arrhythmia following ischemia-reperfusion in aged mouse hearts

2020 ◽  
Author(s):  
◽  
Deborah Peana
Keyword(s):  
Transient Receptor Potential ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Calcium Handling ◽  
Transient Receptor Potential Vanilloid ◽  
Aged Mouse ◽  
Aged Mice ◽  
Hypoosmotic Stress ◽  
Perfused Hearts ◽  
Young Mice

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI--COLUMBIA AT REQUEST OF AUTHOR.] Cardiomyocyte Ca2+ homeostasis is altered with aging and predisposes the Aged heart to Ca2+ intolerance and arrhythmia. Transient Receptor Potential Vanilloid 4 (TRPV4) is an osmotically-activated cation channel and channel expression is increased in cardiomyocytes of Aged mice. The central goal of this work was to determine the role of TRPV4 in calcium handling and arrhythmogenesis in response to hypoosmotic stress and following ischemia-reperfusion (I/R). Hypoosmotic stress induced an increase in calcium transient amplitude in cardiomyocytes isolated from Aged mice which was followed by an increased incidence of arrhythmic Ca2+ events and Ca2+ waves. This effect was prevented by TRPV4 inhibition and was absent in cardiomyocytes from Young mice. Cardiac contractile function, membrane potential, and cardiac ECG was monitored in Langendorff-perfused hearts during I/R. Aged hearts responded to I/R with an initial increase in contractile function, membrane depolarization, and incidence of ventricular arrhythmia during reperfusion. This effect was attenuated by TRPV4 inhibition and was absent in hearts of Young mice. Also, in hearts of Aged, TRPV4 inhibition decreased the percent of damaged tissue following I/R compared to untreated conditions. Finally, Langendorff-perfused hearts from Aged mice expressing a genetically encoded Ca2+ sensor (GCaMP6f) were subjected to I/R and demonstrated an increased Ca2+ transient amplitude and incidence of arrhythmic Ca2+ waves compared to Aged mice treated with TRPV4 inhibition. These findings suggest that TRPV4 may contribute to initial inotropy followed by pro-arrhythmic cardiomyocyte Ca2+ signaling, arrhythmogenesis, and cell death following I/R in the Aged heart.

scholarly journals TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress

2018 ◽  
Vol 115 (1) ◽  
pp. 46-56 ◽  
Author(s):  
John L Jones ◽  
Deborah Peana ◽  
Adam B Veteto ◽  
Michelle D Lambert ◽  
Zahra Nourian ◽  
...  
Keyword(s):  
Protein Expression ◽  
Transient Receptor Potential ◽  
Pathological Condition ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Transient Receptor Potential Vanilloid ◽  
Aged Mice ◽  
Increased Risk ◽  
Hypoosmotic Stress

Abstract Aims Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia–reperfusion (I/R), a pathological condition associated with cardiomyocyte osmotic stress. Methods and results TRPV4 protein expression increased in cardiomyocytes of Aged (24–27 months) mice compared with Young (3–6 months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1 μmol/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4−/−) mice. In Aged, pharmacological inhibition of TRPV4 (1 μmol/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I/R-induced cardiac damage. Conclusions Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.

scholarly journals STAT subtype specificity and ischemic preconditioning in mice: is STAT-3 enough?

2011 ◽  
Vol 300 (2) ◽  
pp. H522-H526 ◽  
Author(s):  
Michael D. Goodman ◽  
Sheryl E. Koch ◽  
Muhammad R. Afzal ◽  
Karyn L. Butler
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Subtype Specificity ◽  
Developed Pressure ◽  
Perfused Hearts

The role of other STAT subtypes in conferring ischemic tolerance is unclear. We hypothesized that in STAT-3 deletion alternative STAT subtypes would protect myocardial function against ischemia-reperfusion injury. Wild-type (WT) male C57BL/6 mice or mice with cardiomyocyte STAT-3 knockout (KO) underwent baseline echocardiography. Langendorff-perfused hearts underwent ischemic preconditioning (IPC) or no IPC before ischemia-reperfusion. Following ex vivo perfusion, hearts were analyzed for STAT-5 and -6 phosphorylation by Western blot analysis of nuclear fractions. Echocardiography and postequilibration cardiac performance revealed no differences in cardiac function between WT and KO hearts. Phosphorylated STAT-5 and -6 expression was similar in WT and KO hearts before perfusion. Contractile function in WT and KO hearts was significantly impaired following ischemia-reperfusion in the absence of IPC. In WT hearts, IPC significantly improved the recovery of the maximum first derivative of developed pressure (+dP/d tmax) compared with that in hearts without IPC. IPC more effectively improved end-reperfusion dP/d tmax in WT hearts compared with KO hearts. Preconditioned and nonpreconditioned KO hearts exhibited increased phosphorylated STAT-5 and -6 expression compared with WT hearts. The increased subtype activation did not improve the efficacy of IPC in KO hearts. In conclusion, baseline cardiac performance is preserved in hearts with cardiac-restricted STAT-3 deletion. STAT-3 deletion attenuates preconditioning and is not associated with a compensatory upregulation of STAT-5 and -6 subtypes. The activation of STAT-5 and -6 in KO hearts following ischemic challenge does not provide functional compensation for the loss of STAT-3. JAK-STAT signaling via STAT-3 is essential for effective IPC.

Abstract 358: Transient Receptor Potential Vanilloid 2 (TRPV2) contributes to myocardial contractility and hypertrophy via sarcoplasmic reticulum calcium handling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jack Rubinstein ◽  
Vivek P Singh ◽  
Valerie M Lasko ◽  
Sheryl E Koch ◽  
Evangelia Kranias ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Fold Increase ◽  
Calcium Handling ◽  
Heart Weight ◽  
Transient Receptor Potential Vanilloid ◽  
Cardiomyocyte Contractility ◽  
Transient Receptor

Background: TRPV2 is a Ca2+ channel that we have recently discovered in cardiomyocytes. The absence of this channel negatively impacts baseline contractility while stimulation results in a positive inotropic response. What remains to be established is the mechanism of this receptor and its role, if any, in the development of hypertrophy. Methods and Results: We obtained isolated cardiomyocytes from wild type (WT) and TRPV2-/- (KO) mice and found that the sarcoplasmic reticulum Ca2+ content and Ca2+ transients were reduced along with fractional shortening in the KO cardiomyocytes (figure, panels A, B, C). In vivo echocardiography confirmed a decrease in ejection fraction in KO mice in comparison to the WT counterparts (panel D). The relevance of these findings was examined in 6 WT and 5 KO mice subjected to transverse aortic constriction (TAC). These mice were followed by echocardiography weekly for a total of 8 weeks post TAC. At the conclusion, the hearts were obtained for histological and molecular analyses. We demonstrated that the KO mice developed less LV hypertrophy in comparison to WT (via echocardiography and by heart weight/body weight ratios) (figure, panels E and F). Importantly, there was a 5 fold increase in TRPV2 expression assessed by PCR in TAC WT hearts, compared to WT not subjected to TAC (0.72±0.10 vs. 0.13±0.04; p<0.01). This suggests a role for TRPV2 not only in contractility, but also in the development of hypertrophy. Conclusions: We have discovered a novel cardiac channel that alters Ca2+ cycling and is capable of modulating cardiomyocyte contractility and hypertrophy, which could lead to novel therapeutic options in heart failure and hypertrophy.

scholarly journals Effects of High Phosphorus Diet on Bone Metabolism-Related Gene Expression in Young and Aged Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Shinichi Katsumata ◽  
Hiroshi Matsuzaki ◽  
Rie Katsumata-Tsuboi ◽  
Mariko Uehara ◽  
Kazuharu Suzuki
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Bone Metabolism ◽  
Transient Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Related Gene ◽  
Aged Mice ◽  
High Phosphorus ◽  
Mrna Ratio ◽  
Rankl Mrna

In this study, the effects of high phosphorus (P) diet on bone metabolism-related gene expression were investigated in young and aged mice. Twelve- and 80-week-old ddY male mice were divided into two groups, respectively, and fed a control diet containing 0.3% P or a high P diet containing 1.2% P. After 4 weeks of treatment, serum parathyroid hormone (PTH) concentration was significantly higher in the high P groups than in the control groups in both young and aged mice and was significantly higher in aged mice than in young mice fed the high P diet. High P diet significantly increased receptor activator of NF-κB ligand (RANKL) mRNA in the femur of both young and aged mice and significantly increased the RANKL/osteoprotegerin (OPG) mRNA ratio only in aged mice. High P diet significantly increased mRNA expression of transient receptor potential vanilloid type 6, calbindin-D9k, and plasma membrane Ca2+-ATPase 1b in the duodenum of both young and aged mice. These results suggest that high P diet increased RANKL mRNA expression in the femur and calcium absorption-related gene expression in the duodenum regardless of age. Furthermore, the high P diet-induced increase in PTH secretion might increase the RANKL/OPG mRNA ratio in aged mice.

scholarly journals Transient Receptor Potential Vanilloid Type 1 Contributes to Modulate the Nitric Oxide Pathway and Oxidative Stress in the Isolated and Perfused Rat Heart during Ischemia and Reperfusion

2021 ◽  
Author(s):  
Vicente Castrejón-Téllez ◽  
Leonardo Del Valle-Mondragón ◽  
Israel Pérez-Torres ◽  
Verónica Guarner-Lans ◽  
Gustavo Pastelín-Hernández ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Histological Evaluation ◽  
Transient Receptor Potential Vanilloid ◽  
Ischemia And Reperfusion ◽  
Cardiac Work ◽  
Western Blots

The transient vanilloid receptor potential type 1 (TRPV1) regulates neuronal and vascular functions mediated by nitric oxide (NO) and by the calcitonin gene-related peptide (CGRP). Here we study the participation of TRPV1 in the regulation of myocardial injury caused by ischemia-reperfusion and in the regulation of NO, tetrahydrobiopterin (BH4), the cGMP pathway, CGRP, total antioxidant capacity (TAC), malondialdehyde (MDA) and phosphodiesterase-3 (PDE-3). Isolated hearts of Wistar rats were used (according to Langendorff) to study the effects of capsaicin (CS), capsazepine (CZ) and CZ+CS treatments. The hearts were divided into three subgroups; 1) perfusion, 2) ischemia and 3) ischemia-reperfusion. In all groups we studied cardiac work and levels of NO, cGMP, BH4, CGRP, TAC, MDA and PDE-3 in ventricular tissue. Western blots were used to determine the expressions of eNOS, iNOS and phosphorylated NOS (pNOS). Structural changes were determined by histological evaluation. CS prevented damage caused by ischemia-reperfusion by improving cardiac work and the levels of NO, cGMP, BH4, TAC and CGRP. TRPV1 and iNOS expression were increased under ischemic conditions, while eNOS and pNOS were not modified. We conclude that the activation of TRPV1 constitutes a therapeutic possibility to counteract the damage caused by ischemia and reperfusion by regulating the NO pathway through CGRP.

scholarly journals Protective Effects of TRPV1 Activation Against Cardiac Ischemia/ Reperfusion Injury is Blunted by Diet-Induced Obesity

2020 ◽  
Vol 20 (2) ◽  
pp. 122-130
Author(s):  
Beihua Zhong ◽  
Shuangtao Ma ◽  
Donna H. Wang
Keyword(s):  
Infarct Size ◽  
Transient Receptor Potential ◽  
Diastolic Pressure ◽  
Gene Knockout ◽  
Ischemia Reperfusion ◽  
Control Diet ◽  
Left Ventricular ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Postischemic Recovery

Background: Activation of Transient Receptor Potential Vanilloid Subtype 1 (TRPV1) channels protects the heart from Ischemia/Reperfusion (I/R) injury through releasing Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP). The current study aimed to study the cardioprotective effects of TRPV1 in obesity. Methods: TRPV1 gene knockout (TRPV1-/-) and Wild-Type (WT) mice were Fed a High-Fat Diet (HFD) or a control diet or for 20 weeks, and then the hearts were collected for I/R injury ex vivo. The hearts were mounted on a Langendorff apparatus and subjected to ischemia (30 min) and reperfusion (40 min) after incubated with capsaicin (10 nmol/L), CGRP (0.1 μmol/L) and SP (0.1 μmol/L). Then, Coronary Flow (CF), left ventricular peak positive dP/dt (+dP/dt), Left Ventricular Developed Pressure (LVDP) and Left Ventricular End-Diastolic Pressure (LVEDP) were measured. Results: HFD intake remarkably reduced CF, +dP/dt and LVDP and elevated LVEDP in both strains (P<0.05). Treatment with capsaicin decreased infarct size, increased CF, +dP/dt and LVDP, and decreased LVEDP in WT mice on control diet (P<0.05), but did not do so in other three groups. Treatment with CGRP and SP decreased infarct size in both strains fed with control diet (P<0.05). In contrast, not all the parameters of cardiac postischemic recovery in HFD-fed WT and TRPV1-/- mice were improved by CGRP and SP. Conclusions: These results suggest that HFD intake impairs cardiac postischemic recovery. HFDinduced impairment of recovery is alleviated by CGRP in both strains and by SP only in TRPV1-/- mice, indicating that the effects of CGRP and SP are differentially regulated during HFD intake.

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