Ranolazine rescues the heart failure phenotype of PLN-deficient human pluripotent stem cell-derived cardiomyocytes

Jiang, Yuliang; Li, Xiaowei; Guo, Tianwei; Lü, Wenjing; Ma, Shuhong; Chang, Yun; Song, Yuanxiu; Zhang, Siyao; Bai, Rui; Wang, Hongyue; Qi, Man; Jiang, Hongfeng; Zhang, Hongjia; Lan, Feng

doi:10.1016/j.stemcr.2022.02.016

Cited by 7 publications

(10 citation statements)

References 43 publications

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“…The present results show that ROS and CaMKII signaling (well‐known I NaL enhancers) was unperturbed at the pre‐symptomatic stage of the mutation, thus suggesting that hyperdynamic Ca 2+ handling per se may be inadequate to enhance I NaL . The view that PLN loss of function may be harmful on the long run is also supported by its association with ACM in human mutations, 23 by the observation that PLN‐sarcolipin double knock‐out triggers hypertrophic remodeling 24 and by the significant derangements occurring 2 months after PLN knock‐out in hiPS‐CMs 22 . Altogether, these findings indicate that constitutively unrestrained SERCA2a function may, in the long term, have a negative impact on myocyte biology.…”

Section: Discussionmentioning

confidence: 89%

“…The present results suggest instead that PLN R14del +/− loses the ability to inhibit SERCA2a; the resulting “hyperdynamic” Ca 2+ handling might look less plausible as a cause of reduced contractility. PLN knockout, and the resulting “hyperdynamic state” of Ca 2+ handling, may be well tolerated in TG mice; 21 nonetheless, it may lead to overt cardiomyopathy over longer time spans in hiPS‐CMs 22 . In the latter case, cellular derangements were supported by I NaL enhancement, 22 but it was unclear whether this represented a primary mutation effect.…”

Section: Discussionmentioning

confidence: 99%

“…PLN knockout, and the resulting “hyperdynamic state” of Ca 2+ handling, may be well tolerated in TG mice; 21 nonetheless, it may lead to overt cardiomyopathy over longer time spans in hiPS‐CMs 22 . In the latter case, cellular derangements were supported by I NaL enhancement, 22 but it was unclear whether this represented a primary mutation effect. The present results show that ROS and CaMKII signaling (well‐known I NaL enhancers) was unperturbed at the pre‐symptomatic stage of the mutation, thus suggesting that hyperdynamic Ca 2+ handling per se may be inadequate to enhance I NaL .…”

Section: Discussionmentioning

confidence: 99%

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Early consequences of the phospholamban mutation PLN‐R14del^+/− in a transgenic mouse model

Maniezzi,

Eskandr,

Florindi

et al. 2024

Acta Physiologica

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AimsThe heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/−) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. “Superinhibition” of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected.MethodsCa2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8–12 weeks‐old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated.ResultsThe mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress.Conclusions(1) PLN R14del+/− loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Early consequences of the phospholamban mutation PLN‐R14del^+/− in a transgenic mouse model

Maniezzi,

Eskandr,

Florindi

et al. 2024

Acta Physiologica

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“…Notably, the metabolic response to PLN knock out in hiPS-CMs is a transient increase in OCR, with mitochondrial damage appearing only as a late consequence. 28 Both PLN R14del +/and PLN knock out induce a hyperdynamic state, but in the latter PLN protein is missing. This may suggest an additional pathogenetic mechanism, independent from changes in SERCA2a function: ACM might result from toxicity of the mutant protein.…”

Section: Discussionmentioning

confidence: 99%

“…25 However, some human mutations with PLN loss of function are associated with ACM, 26 PLN-sarcolipin double knock-out mice undergo hypertrophic remodeling 27 and significant derangements occur 2 months after PLN knock out in hiPS-CMs. 28 This suggests that constitutively unrestrained SERCA2a function may, in the long term, have a negative impact on myocyte biology. Notably, clinical ACM is indeed of late onset in PLN R14del +/carriers.…”

Section: Intracellular Ca 2+ Dynamicsmentioning

confidence: 99%

Early consequences of the phospholamban mutation PLN-R14del^+/-in a transgenic mouse model

Maniezzi

Eskandr

Florindi

et al. 2023

Preprint

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Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/-) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. "Superinhibition" of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to 1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; 2) to test whether they are causally connected. Methods and Results: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy and redox homeostasis were measured in ventricular myocytes of 8-12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analysed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signalling pathways were evaluated. The mutation was characterized by hyperdynamic Ca2+ handling, similar to that induced by PLN antagonism. Albeit all components of energy metabolism were depressed at rest, functional signs of mitochondrial damage or energy starvation were absent and cell energy charge was preserved. The response of mitochondrial O2 consumption to SERCA2a blockade was lost in mutant myocytes (SR-mitochondrial uncoupling) and ER-stress signalling was activated. Conclusions: 1) PLN R14del+/- loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a mechanism of ACM; 2) depression of resting energy metabolism may at least partly reflect impairment of SR-mitochondrial coupling; 3) ER-stress may be an early factor in the pathogenesis.

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The role of cardiac microenvironment in cardiovascular diseases: implications for therapy

Yao,

Chen,

Huang

et al. 2024

Human Cell

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Ranolazine rescues the heart failure phenotype of PLN-deficient human pluripotent stem cell-derived cardiomyocytes

Cited by 7 publications

References 43 publications

Early consequences of the phospholamban mutation PLN‐R14del^+/− in a transgenic mouse model

Early consequences of the phospholamban mutation PLN‐R14del^+/− in a transgenic mouse model

Early consequences of the phospholamban mutation PLN-R14del^+/-in a transgenic mouse model

The role of cardiac microenvironment in cardiovascular diseases: implications for therapy

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Ranolazine rescues the heart failure phenotype of PLN-deficient human pluripotent stem cell-derived cardiomyocytes

Cited by 7 publications

References 43 publications

Early consequences of the phospholamban mutation PLN‐R14del+/− in a transgenic mouse model

Early consequences of the phospholamban mutation PLN‐R14del+/− in a transgenic mouse model

Early consequences of the phospholamban mutation PLN-R14del+/-in a transgenic mouse model

The role of cardiac microenvironment in cardiovascular diseases: implications for therapy

Contact Info

Product

Resources

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Early consequences of the phospholamban mutation PLN‐R14del^+/− in a transgenic mouse model

Early consequences of the phospholamban mutation PLN‐R14del^+/− in a transgenic mouse model

Early consequences of the phospholamban mutation PLN-R14del^+/-in a transgenic mouse model