The Control of Diastolic Calcium in the Heart

Eisner, David; Caldwell, Jessica L.; Trafford, Andrew W.; Hutchings, David

doi:10.1161/circresaha.119.315891

Cited by 114 publications

(64 citation statements)

References 188 publications

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“…Whereas the ISO-evoked increase of the Ca 2+ transient was significantly larger in TRPM4 −/− cardiomyocytes in the 129SvJ strain compared to TRPM4 +/+ controls, which reinforces our previous analysis [21], we could not find a significant difference between the two genotypes in the C57Bl/6 N background. In our attempts to gain mechanistic insights into the differences in TRPM4dependent Ca 2+ signaling between the two strains, we analysed protein expression of the L-Type Ca 2+ channel subunit Ca V β 2 and SERCA2a proteins, whose expression level and activity regulate diastolic SR Ca 2+ load [7]. However, our findings show neither divergences in Ca V β 2 and SERCA2a protein expression nor differences in caffeine-induced SR Ca 2+ depletion in cardiomyocytes from 129SvJ compared to C57Bl/6N mice indicating that SR Ca 2+ load is not different in ventricular cardiomyocytes between the strains.…”

Section: Discussionmentioning

confidence: 99%

Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

et al. 2020

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Transient receptor potential melastatin 4 (TRPM4) cation channels act in cardiomyocytes as a negative modulator of the L-type Ca2+ current. Ubiquitous Trpm4 deletion in mice leads to an increased β-adrenergic inotropy in healthy mice as well as after myocardial infarction. In this study, we set out to investigate cardiac inotropy in mice with cardiomyocyte-specific Trpm4 deletion. The results guided us to investigate the relevance of TRPM4 for catecholamine-evoked Ca2+ signaling in cardiomyocytes and inotropy in vivo in TRPM4-deficient mouse models of different genetic background. Cardiac hemodynamics were investigated using pressure–volume analysis. Surprisingly, an increased β-adrenergic inotropy was observed in global TRPM4-deficient mice on a 129SvJ genetic background, but the inotropic response was unaltered in mice with global and cardiomyocyte-specific TRPM4 deletion on the C57Bl/6N background. We found that the expression of TRPM4 proteins is about 78 ± 10% higher in wild-type mice on the 129SvJ versus C57Bl/6N background. In accordance with contractility measurements, our analysis of the intracellular Ca2+ transients revealed an increase in ISO-evoked Ca2+ rise in Trpm4-deficient cardiomyocytes of the 129SvJ strain, but not of the C57Bl/6N strain. No significant differences were observed between the two mouse strains in the expression of other regulators of cardiomyocyte Ca2+ homeostasis. We conclude that the relevance of TRPM4 for cardiac contractility depends on homeostatic TRPM4 expression levels or the genetic endowment in different mouse strains as well as on the health/disease status. Therefore, the concept of inhibiting TRPM4 channels to improve cardiac contractility needs to be carefully explored in specific strains and species and prospectively in different genetically diverse populations of patients.

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Section: Discussionmentioning

confidence: 99%

Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

et al. 2020

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“…In support of this mechanism, istaroxime, a newer intracellular Na + enhancer, has been demonstrated to improve both diastolic and systolic function in patients with decompensated HF with reduced ejection fraction (HFrEF), along with increasing systolic blood pressure while reducing heart rate, with no evidence of increases in the probability of cardiac arrhythmias [100][101][102][103]. Notwithstanding this, a note of caution must be taken concerning intracellular Na + overload as a consequence of chronic P2X4R activation, since increases in diastolic Ca 2+ concentration may worsen the diastolic dysfunction in HF conditions [104]. Another caveat is related to rhythm disturbances that may arise from perturbations of Na + and Ca 2+ -handling resulting from prolonged activation of the P2X4R.…”

Section: Benefits From the P2x4 Receptor Activation In The Heartmentioning

confidence: 99%

Resolving the Ionotropic P2X4 Receptor Mystery Points towards a New Therapeutic Target for Cardiovascular Diseases

Bragança

Correia-de-Sá

2020

IJMS

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Adenosine triphosphate (ATP) is a primordial versatile autacoid that changes its role from an intracellular energy saver to a signaling molecule once released to the extracellular milieu. Extracellular ATP and its adenosine metabolite are the main activators of the P2 and P1 purinoceptor families, respectively. Mounting evidence suggests that the ionotropic P2X4 receptor (P2X4R) plays pivotal roles in the regulation of the cardiovascular system, yet further therapeutic advances have been hampered by the lack of selective P2X4R agonists. In this review, we provide the state of the art of the P2X4R activity in the cardiovascular system. We also discuss the role of P2X4R activation in kidney and lungs vis a vis their interplay to control cardiovascular functions and dysfunctions, including putative adverse effects emerging from P2X4R activation. Gathering this information may prompt further development of selective P2X4R agonists and its translation to the clinical practice.

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“…Deterioration in contractile mechanics of a heart that is hypertrophied, dilated, or fibrotic correlates with altered excitation-contraction coupling and failing bioenergetics (Franz et al, 1992;Nishimura et al, 2006). Contractile force generation requires calcium signaling; while intracellular SR calcium is reviewed in detail elsewhere (Eisner et al, 2020), in this section, we will specifically provide a brief overview of mitochondrial calcium handling. Mitochondrial calcium dynamics are determined by ATP/ADP ratio, transporter expression levels, and other regulatory signals (Zhou and Tian, 2018).…”

Section: Pathological Mitochondrial Function Mitochondrial Calcium Handlingmentioning

confidence: 99%

Changes in Myocardial Metabolism Preceding Sudden Cardiac Death

et al. 2020

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Heart disease is widely recognized as a major cause of death worldwide and is the leading cause of mortality in the United States. Centuries of research have focused on defining mechanistic alterations that drive cardiac pathogenesis, yet sudden cardiac death (SCD) remains a common unpredictable event that claims lives in every age group. The heart supplies blood to all tissues while maintaining a constant electrical and hormonal feedback communication with other parts of the body. As such, recent research has focused on understanding how myocardial electrical and structural properties are altered by cardiac metabolism and the various signaling pathways associated with it. The importance of cardiac metabolism in maintaining myocardial function, or lack thereof, is exemplified by shifts in cardiac substrate preference during normal development and various pathological conditions. For instance, a shift from fatty acid (FA) oxidation to oxygen-sparing glycolytic energy production has been reported in many types of cardiac pathologies. Compounded by an uncoupling of glycolysis and glucose oxidation this leads to accumulation of undesirable levels of intermediate metabolites. The resulting accumulation of intermediary metabolites impacts cardiac mitochondrial function and dysregulates metabolic pathways through several mechanisms, which will be reviewed here. Importantly, reversal of metabolic maladaptation has been shown to elicit positive therapeutic effects, limiting cardiac remodeling and at least partially restoring contractile efficiency. Therein, the underlying metabolic adaptations in an array of pathological conditions as well as recently discovered downstream effects of various substrate utilization provide guidance for future therapeutic targeting. Here, we will review recent data on alterations in substrate utilization in the healthy and diseased heart, metabolic pathways governing cardiac pathogenesis, mitochondrial function in the diseased myocardium, and potential metabolism-based therapeutic interventions in disease.

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The Control of Diastolic Calcium in the Heart

Cited by 114 publications

References 188 publications

Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

Resolving the Ionotropic P2X4 Receptor Mystery Points towards a New Therapeutic Target for Cardiovascular Diseases

Changes in Myocardial Metabolism Preceding Sudden Cardiac Death

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