Angiotensin II induces apoptosis in human induced pluripotent stem cell-derived cardiomyocytes

Gao, Qiang; Wang, Ping; Wu, Zhiming; Qiu, Hailong; Lin, Bin; Chen, Jimei; Cen, Jianzheng; Zhuang, Jian

doi:10.1101/2020.03.19.998344

Cited by 3 publications

(3 citation statements)

References 80 publications

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“…This concentration has been reported to affect cardiac activities [51] but is not fatal to cardiomyocytes [52] . Indeed, more cells underwent apoptosis and necrosis and more cells showed abnormal nuclear morphology.…”

Section: Discussionmentioning

confidence: 86%

“…This concentration has been reported to affect cardiac activities [ 51 ] but is not fatal to cardiomyocytes. [ 52 ] Indeed, more cells underwent apoptosis and necrosis and more cells showed abnormal nuclear morphology in the presence of Ang II. After a short period of incubation, however, the majority of the cells were alive and kept beating.…”

Section: Discussionmentioning

confidence: 99%

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Sars‐Cov‐2 Spike Protein‐Induced Damage of hiPSC‐Derived Cardiomyocytes

Huang

et al. 2022

Advanced Biology

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Sars-Cov-2 may trigger molecular and functional alterations of cardiomyocytes of the heart due to the presence of receptor angiotensin-converting enzyme 2 (ACE2) of the host cells. While the endocytic itinerary of the virus via cleavage of the spike protein of Sars-Cov-2 is well understood, the role of the remaining part of the spike protein subunit and ACE2 complex is still elusive. Herein, we investigate the possible effects of this complex by using synthetic spike proteins of Sars-Cov-2, human induced pluripotent stem cells (hiPSC), and a culture device made of an arrayed monolayer of crosslinked nanofibers. hiPSCs were firstly differentiated into cardiomyocytes (CM) which formed cardiac tissue-like constructs with regular beating and expression of both ACE2 and gap junction protein Connexin 43. When incubated with the spike proteins, the hiPSC-CMs underwent a rhythmic fluctuation with overstretched sarcomere structures and dispersed gap junction proteins. When incubated with the spike proteins and supplementary Angiotensin II, the damage of the spike protein on hiPSC-CMs was enhanced due to downregulated ACE2, chromatin margination, altered Connexin 43 expression, sarcomere disruption, and beating break. This discovery may imply latent effects of the spike proteins on the heart.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Sars‐Cov‐2 Spike Protein‐Induced Damage of hiPSC‐Derived Cardiomyocytes

Huang

et al. 2022

Advanced Biology

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“…Oxygen Species (ROS) triggered pathways (Harsdorf et al, 1999), angiotensin II pathway (Cigola et al, 1997;Kajstura et al, 1997;Gao et al, 2020), sympathetic stimulation (Adams et al, 1998;Singh et al, 2000) or cytokines triggered pathways (Arstall et al, 1999;Oka & Komuro, 2008). In addition to apoptosis, excessive autophagy and necrosis also causes the loss of cardiomyocytes (Kostin et al, 2003;Nakayama et al, 2007;Oka & Komuro, 2008).…”

Section: Apoptosis Of Cardiomyocytes Can Also Be Induced By Several O...mentioning

confidence: 99%

The role of CRISPLD1 in the transition to heart failure

Hindmarsh¹

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Heart failure is a leading cause of death worldwide. It is defined as a condition in which the heart is unable to pump a sufficient amount of blood through the body to satisfy its oxygen need and can be caused by various cardiac diseases. Although several mechanisms are already identified to play a role in the transition to HF, there is still a lack of knowledge about the precise mechanisms. To gain better insights into these mechanisms, previous studies in the group performed RNA-sequencing of human myocardium samples from patients suffering from aortic stenosis with compensated hypertrophy or heart failure. The obtained dataset was compared to data from analogous progression stages in the transverse aortic constriction mouse model to identify novel target genes in the disease. Among these genes, CRISPLD1showed conserved expression levels and was upregulated during the transition to heart failure in human and mouse. Protein structure analysis identified a V5/Tpx-1 related conserved site which is known to be evolutionary related to the toxin helothermine, that regulates calcium homeostasis. To elucidate the function of CRISPLD1 in the heart, induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and two knockout mouse models were analyzed.CRISPLD1-deficient iPSC-CMs were generated via CRISPR/Cas9 and showed dysregulation of calcium handling. Transcriptome analysis of these cells revealed a downregulation of prohypertrophic, proapoptotic and calcium-regulating pathways, suggesting CRISPLD1 loss-offunction as being beneficial in response to cardiomyocyte stress. However, analysis of Crispld1-deficient knockout mouse lines showed contrary results. While the ubiquitous Crispld1 knockout mouse line did not show any phenotype, the heart-specific Crispld1 knockout mouse line displayed a severe dilated cardiac phenotype with increased mortality.Analysis of hypertrophic markers, measurement of cardiomyocyte hypertrophy or fibrosis did not indicate any alterations. Even more, calcium cycling evaluations of isolated mouse cardiomyocytes could not confirm the findings of iPSC-CMs and again no alterations comparing the mouse lines were observed. Although, the severe cardiac phenotype of heartspecific Crispld1 knockout mice could not be explained, results obtained in cell culture were promising and identified CRISPLD1 as playing a role in calcium cycling in CMs. In conclusion, the findings from this thesis give first insights into the potential role of CRISPLD1 as a calcium regulator in the heart in a human and murine model system. However, future research is necessary to identify its specific role and explain the severe mouse phenotype.HF is defined as a condition in which the heart is unable to pump a sufficient amount of blood to supply the body with oxygen. Various cardiac conditions and pathologies such as congenital heart diseases, coronary ischemia, chronic hypertension and many more can result in HF

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An Insight on Multicentric Signaling of Angiotensin II in Cardiovascular system: A Recent Update

et al. 2021

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The multifaceted nature of the renin-angiotensin system (RAS) makes it versatile due to its involvement in pathogenesis of the cardiovascular disease. Angiotensin II (Ang II), a multifaceted member of RAS family is known to have various potential effects. The knowledge of this peptide has immensely ameliorated after meticulous research for decades. Several studies have evidenced angiotensin I receptor (AT1 R) to mediate the majority Ang II-regulated functions in the system. Functional crosstalk between AT1 R mediated signal transduction cascades and other signaling pathways has been recognized. The review will provide an up-to-date information and recent discoveries involved in Ang II receptor signal transduction and their functional significance in the cardiovascular system for potential translation in therapeutics. Moreover, the review also focuses on the role of stem cell-based therapies in the cardiovascular system.

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Angiotensin II induces apoptosis in human induced pluripotent stem cell-derived cardiomyocytes

Cited by 3 publications

References 80 publications

Sars‐Cov‐2 Spike Protein‐Induced Damage of hiPSC‐Derived Cardiomyocytes

Sars‐Cov‐2 Spike Protein‐Induced Damage of hiPSC‐Derived Cardiomyocytes

The role of CRISPLD1 in the transition to heart failure

An Insight on Multicentric Signaling of Angiotensin II in Cardiovascular system: A Recent Update

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