Depressed contractile function and adrenergic responsiveness of cardiac myocytes in an experimental model of Parkinson disease, the MPTP-treated mouse

2004 ◽  
Vol 25 (1) ◽  
pp. 131-138 ◽  
Author(s):  
Jun Ren ◽  
James E. Porter ◽  
Loren E. Wold ◽  
Nicholas S. Aberle ◽  
Dhanasekaran Muralikrishnan ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Experimental Model ◽  
Cardiac Myocytes ◽  
Contractile Function ◽  
Treated Mouse

Abstract 99: Hypotonic Swelling Promotes Nitric Oxide Release in Cardiac Ventricular Myocytes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Luis Gonano ◽  
Malena Morell ◽  
Juan I Burgos ◽  
Martin Vila Petroff
Keyword(s):  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Cell Swelling ◽  
Contractile Dysfunction ◽  
Ischemia And Reperfusion ◽  
Hypotonic Solution ◽  
No Release ◽  
Hypotonic Swelling

Cardiac myocyte swelling occurs in multiple pathological situations and in particular contributes to the deleterious effects of ischemia and reperfusion by promoting contractile dysfunction. We investigated whether hypotonic swelling promotes nitric oxide (NO) release in cardiac myocytes and if so, whether it impacts on swelling induced contractile dysfunction. Perfusing rat cardiac myocytes, loaded with the NO sensor DAF-FM, with a hypotonic solution (HS; 217 mOsm), increased cell volume, reduced myocyte contraction and Ca2+ transient amplitude and significantly increased DAF-FM fluorescence. When cells were exposed to the HS supplemented with 2.5 mM of the NO synthase inhibitor L-NAME, cell swelling occurred in the absence of NO release. Swelling-induced NO release was also prevented by the NOS1 inhibitor, Nitroguanidine. In addition, Colchicine (an inhibitor of microtubule polymerization) prevented the increase in DAF-FM fluorescence induced by HS indicating that microtubule integrity is necessary for swelling-induced NO release. The swelling-induced negative inotropic effect was exacerbated in the presence of either L-NAME, Nitroguandine or the guanylate cyclase inhibitor, ODQ, suggesting that NOS1-derived NO provides contractile support via a GMP-dependent mechanism. Indeed, ODQ reduced Ca2+ wave velocity and the HS-induced increment in ryanodine receptor (RyR2) phosphorylation at site Ser2808 suggesting that in the context of hypotonic swelling, cGMP may contribute to preserve contractile function by enhancing SR Ca2+ release. Our findings suggest a novel mechanism for NO release in cardiac myocytes with putative pathophysiological relevance in the context of ischemia and reperfusion, where it may be cardioprotective by reducing the extent of contractile dysfunction associated with hypotonic swelling.

Endothelin-1 ameliorates contractile depression by lipopolysaccharide in cardiac myocytes

1997 ◽  
Vol 273 (3) ◽  
pp. H1403-H1407 ◽  
Author(s):  
S. Yasuda ◽  
W. Y. Lew
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cardiac Myocytes ◽  
Contractile Function ◽  
Adult Rabbit ◽  
Nitric Oxide Synthase Inhibitor ◽  
Endothelin 1 ◽  
Cardiac Depression ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Lipopolysaccharide (LPS) induces cardiac depression by activating nitric oxide pathways to increase guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of nitric oxide. Endothelin-1 (ET-1) may interact with nitric oxide pathways. We hypothesized that ET-1 modulates LPS-induced contractile depression in cardiac myocytes. Adult rabbit cardiac myocytes exposed to LPS (10 ng/ml) developed decreased cell shortening after 6 h, with an increase in cardiac cGMP levels [606 +/- 36 (SE) fmol/mg protein] compared with control myocytes (360 +/- 26 fmol/mg protein, P < 0.05). LPS effects were completely blocked by coincubation with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (1 mM). Coincubation with ET-1 (10 nM) attenuated the contractile depression and increase in cGMP with LPS (482 +/- 28 fmol/mg protein, P < 0.05 vs. LPS alone). ET-1 alone did not alter cGMP levels (350 +/- 30 fmol/mg protein). ET-1 effects on contractile function were blocked by BQ-123 (10 microM), a selective ET-1 type A receptor antagonist. We conclude that ET-1 ameliorates LPS-induced contractile depression in cardiac myocytes by attenuating LPS effects on nitric oxide-cGMP pathways.

scholarly journals A Critical Role for Estrogen-Related Receptor Signaling in Cardiac Maturation

2020 ◽  
Vol 126 (12) ◽  
pp. 1685-1702 ◽  
Author(s):  
Tomoya Sakamoto ◽  
Timothy R. Matsuura ◽  
Shibiao Wan ◽  
David M. Ryba ◽  
J`unil Kim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Critical Role ◽  
Functional Characterization ◽  
Induced Pluripotent Stem Cell ◽  
Gene Markers ◽  
Cardiac Maturation ◽  
Estrogen Related Receptor

Rationale: The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the fetal shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell–derived cardiac myocytes. Objective: To delineate transcriptional drivers of cardiac maturation. Methods and Results: We hypothesized that ERR (estrogen-related receptor) α and γ, known transcriptional regulators of postnatal mitochondrial biogenesis and function, serve a role in the broader cardiac maturation program. We devised a strategy to knockdown the expression of ERRα and γ in heart after birth (pn-csERRα/γ [postnatal cardiac-specific ERRα/γ]) in mice. With high levels of knockdown, pn-csERRα/γ knockdown mice exhibited cardiomyopathy with an arrest in mitochondrial maturation. RNA sequence analysis of pn-csERRα/γ knockdown hearts at 5 weeks of age combined with chromatin immunoprecipitation with deep sequencing and functional characterization conducted in human induced pluripotent stem cell–derived cardiac myocytes (hiPSC-CM) demonstrated that ERRγ activates transcription of genes involved in virtually all aspects of postnatal developmental maturation, including mitochondrial energy transduction, contractile function, and ion transport. In addition, ERRγ was found to suppress genes involved in fibroblast activation in hearts of pn-csERRα/γ knockdown mice. Disruption of Esrra and Esrrg in mice during fetal development resulted in perinatal lethality associated with structural and genomic evidence of an arrest in cardiac maturation, including persistent expression of early developmental and noncardiac lineage gene markers including cardiac fibroblast signatures. Lastly, targeted deletion of ESRRA and ESRRG in hiPSC-CM derepressed expression of early (transcription factor 21 or TCF21) and mature (periostin, collagen type III) fibroblast gene signatures. Conclusions: ERRα and γ are critical regulators of cardiac myocyte maturation, serving as transcriptional activators of adult cardiac metabolic and structural genes, an.d suppressors of noncardiac lineages including fibroblast determination.

scholarly journals sGCα1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling

2011 ◽  
Vol 301 (1) ◽  
pp. H157-H163 ◽  
Author(s):  
Sharon M. Cawley ◽  
Starsha Kolodziej ◽  
Fumito Ichinose ◽  
Peter Brouckaert ◽  
Emmanuel S. Buys ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Soluble Guanylate Cyclase ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Spermine Nonoate ◽  
Brl 37344

In the heart, nitric oxide (NO) modulates contractile function; however, the mechanisms responsible for this effect are incompletely understood. NO can elicit effects via a variety of mechanisms including S-nitrosylation and stimulation of cGMP synthesis by soluble guanylate cyclase (sGC). sGC is a heterodimer comprised of a β1- and an α1- or α2-subunit. sGCα1β1 is the predominant isoform in the heart. To characterize the role of sGC in the regulation of cardiac contractile function by NO, we compared left ventricular cardiac myocytes (CM) isolated from adult mice deficient in the sGC α1-subunit (sGCα1−/−) and from wild-type (WT) mice. Sarcomere shortening under basal conditions was less in sGCα1−/− CM than in WT CM. To activate endogenous NO synthesis from NO synthase 3, CM were incubated with the β3-adrenergic receptor (β3-AR) agonist BRL 37344. BRL 37344 decreased cardiac contractility in WT CM but not in sGCα1−/− myocytes. Administration of spermine NONOate, an NO donor compound, did not affect sarcomeric shortening in CM of either genotype; however, in the presence of isoproterenol, addition of spermine NONOate reduced sarcomere shortening in WT but not in sGCα1−/− CM. Neither BRL 37344 nor spermine NONOate altered calcium handling in CM of either genotype. These findings suggest that sGCα1 exerts a positive inotropic effect under basal conditions, as well as mediates the negative inotropic effect of β3-AR signaling. Additionally, our work demonstrates that sGCα1β1 is required for NO to depress β1/β2-AR-stimulated cardiac contractility and that this modulation is independent of changes in calcium handling.

Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of α-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility

2005 ◽  
Vol 288 (3) ◽  
pp. H1477-H1490 ◽  
Author(s):  
Francesca J. Davis ◽  
Jyothish B Pillai ◽  
Madhu Gupta ◽  
Mahesh P. Gupta
Keyword(s):  
Cardiac Myocytes ◽  
Histone Deacetylases ◽  
Contractile Function ◽  
Trichostatin A ◽  
In Vivo Model ◽  
Ang Ii ◽  
Cardiac Contractile Function ◽  
Noticeable Effect

Histone deacetylases (HDACs) are a family of enzymes that catalyze the removal of acetyl groups from core histones, resulting in change of chromatin structure and gene transcription activity. In the heart, HDACs are targets of hypertrophic signaling, and their nonspecific inhibition by trichostatin A (TSA) attenuates hypertrophy of cultured cardiac myocytes. In this study, we examined the effect of TSA on two major determinants of cardiac contractility: α-myosin heavy chain (MHC) expression and microtubular composition and organization. TSA upregulated the expression of α-MHC in cultured cardiac myocytes, as well as in an in vivo model of hypothyroid rats. Studies designed to delineate mechanisms of α-MHC induction by TSA revealed an obligatory role of early growth response factor-1 on activation of the α-MHC promoter. Concurrently, TSA downregulated the expression of α- and β-tubulins and prevented the induction of tubulins by a hypertrophy agonist, ANG II. The ANG II-mediated increased proportion of α- and β-tubulins associated with polymerized microtubules was also markedly reduced after treatment of cells by TSA. Results obtained from immunofluorescent microscopy indicated that TSA had no noticeable effect on the organization of cardiac microtubules in control cells, whereas it prevented the ANG II-induced dense parallel linear arrays of microtubules to a profile similar to that of controls. Together, these results demonstrate that inhibition of HDACs by TSA regulates the cardiac α-MHC and tubulins in a manner predictive of improved cardiac contractile function. These studies improve our understanding of the role of HDACs on cardiac hypertrophy with implications in development of new therapeutic agents for treatment of cardiac abnormalities.

scholarly journals PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

2016 ◽  
Vol 113 (45) ◽  
pp. E7116-E7125 ◽  
Author(s):  
Walter E. Knight ◽  
Si Chen ◽  
Yishuai Zhang ◽  
Masayoshi Oikawa ◽  
Meiping Wu ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Causative Role ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Cardiac Myocyte Hypertrophy

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.

Hibernating myocardium: pathophysiology, diagnosis, and treatmentThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue).

2009 ◽  
Vol 87 (4) ◽  
pp. 252-265 ◽  
Author(s):  
Jan Slezak ◽  
Narcis Tribulova ◽  
Ludmila Okruhlicova ◽  
Rimpy Dhingra ◽  
Anju Bajaj ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Myocytes ◽  
Contractile Function ◽  
Blood Perfusion ◽  
Accurate Diagnosis ◽  
Hibernating Myocardium ◽  
Omega 3 ◽  
Structural Adaptation ◽  
Chronic Ischemia ◽  
Pattern Of Injury

Comprehensive management of patients with chronic ischemic disease is a critically important component of clinical practice. Cardiac myocytes have the potential to adapt to limited flow conditions by adjusting contractile function, reducing metabolism, conserving resources, and preserving myocardial integrity to cope with an oxygen and (or) nutrition shortage. A prime metabolic feature of cardiac myocytes affected by chronic ischemia is the return to a fetal gene pattern with predominance of carbohydrates as the substrate for energy. Structural adaptation with multiple intracellular changes is part of the remodeling process in hibernating myocardium. Transmural heterogeneity, which defines the pattern of injury in ventricular cardiomyocytes and the response to chronic ischemia, is a multifactorial process originating from functional, metabolic, and flow differences in subendocardial and subepicardial regions. Autophagy is typically activated in hibernating myocardium and has been identified as a prosurvival mechanism. Chronic ischemia is associated with changes in the number, size, and distribution of gap junctions and may give rise to conduction disturbances and arrhythmogenesis. Differentiation between viable and nonviable myocardium by assessing sensitivity of inotropic reserve is a crucial diagnostic tool that is correlated with the prognosis and outcome for improved contractility after restoration of blood perfusion in afflicted myocardium.Reliable and accurate diagnosis of ischemic, scar, and viable tissues is critical for recover strategies. Although early surgical reinstitution of blood flow is most effective in restoring physiologic function of the hibernating myocardium, several new approaches offer promising alternatives. Among others, vascular endothelial growth factor and fibroblast growth factor-2 (FGF-2), especially its lo-FGF-2 isoform, have been shown to be effective in rapid neovascularization. Substances such as statins, resveratrol, some hormones, and omega-3 fatty acids can improve recovery effect in chronically underperfused hearts. For patients with drug-refractory ischemia, intramyocardial transplantation of stem cells into predefined areas of the heart can enhance vascularization and have beneficial effects on cardiac function. This review of ischemic injury, its heterogeneity, accurate diagnosis, and newer methods of treatment, shows there is much information and tremendous hope for better management of patients with coronary heart disease.

Sign in / Sign up

Export Citation Format

Share Document