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Cardiovascular consequences of K(ATP) dysfunction in Cantu Syndrome arising from in mutations Kir6.1 (KCNJ8) and SUR2 (ABCC9)

ABSTRACT: Cardiovascular consequences of K(ATP) dysfunction in Cantu Syndrome arising from in mutations Kir6.1 (KCNJ8) and SUR2 (ABCC9)

PROVIDER: PRJNA434080 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6726060.fastq.gz	Fastqsanger.gz
	SRR6726070.fastq.gz	Fastqsanger.gz
	SRR6726080.fastq.gz	Fastqsanger.gz
	SRR6726061.fastq.gz	Fastqsanger.gz
	SRR6726071.fastq.gz	Fastqsanger.gz

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Cardiovascular consequences of K(ATP) dysfunction in Cantu Syndrome arising from in mutations Kir6.1 (KCNJ8) and SUR2 (ABCC9)

Project description:Cantu Syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) K(ATP) channel subunits. We generated mice carrying CS-associated SUR2[A478V] and Kir6.1[V65M] mutations, knocked in to the endogenous loci using CRISPR/Cas9 engineering. Mirroring human CS, both of these animals have low systemic blood pressure and dilated, compliant blood vessels, as well as dramatically enlarged hearts with increased contractility. Whole-cell patch-clamp recording reveal enhanced basal K(ATP) conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure. Echocardiography confirms in situ cardiac enlargement, with increased contractility and maintained ejection fraction. Whole-cell voltage clamp of ventricular myocytes reveals increased basal L-type Ca2+ current (LTCC), explaining enhanced contractility. Cardiac hypertrophy and enhanced contractility may arise as secondary compensation, to maintain tissue perfusion in the presence of marked vascular dilation. All of the above features are more prominent in Kir6.1[V65M] animals than in SUR2[A478V] animals, and exacerbated in homozygous animals of each genotype. Compensatory mechanisms are likely to be limiting, since survival is inversely correlated with severity of the phenotype, with very early death in homozygous Kir6.1[V65M] animals. The SUR2[A478V] and Kir6.1[V65M] animals reiterate and explain cardiovascular features in human CS, and raise concerns regarding the long-term consequences of CS specifically, and reduced smooth muscle tone in general.

2020-02-04 | GSE110592 | GEO

Mitochondrial dysfunction and consequences in calpain-3-deficient muscle

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Malnutrition-associated hepatic steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction and rescued by fenofibrate

Project description:Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. To investigate the underlying mechanisms of hepatic dysfunction we used a rat model of malnutrition by placing weanling rats on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Low protein diet-fed rats developed hypoalbuminemia and severe hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated impaired peroxisomal function. Loss of peroxisomes was followed by accumulation of dysfunctional mitochondria and decreased hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial fatty acid β-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. These findings provide important insight into the metabolic disturbances associated with malnutrition and have potentially profound clinical consequences with respect to the management of malnourished children worldwide.

2016-06-18 | GSE63096 | GEO

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Project description:Cardiovascular diseases (CVD) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, sPCSK9 correlated positively with increasing age and the development of cardiovascular dysfunction. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats suggesting that PCSK9 plays an important role in cardiovascular aging.

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PCSK9, a promising novel target for age-related cardiovascular dysfunction

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Modeling Radiation-induced Cardiovascular Dysfunction with Human iPSC-Derived Engineered Heart Tissues

Project description:Low-LET radiation can cause cardiovascular dysfunctions at high-dose rates. For example, photons used in thoracic radiotherapy are known to cause acute cardiac tissue damage with elevated serum cardiac Troponin I level and long-term cardiac complications when delivered as fractionated exposures at high-dose rates. However, the effects of continuous low-dose rate radiation exposure on the heart, which simulate the space radiation environment, have not been well-studied. In this study, we aim to model low-LET space radiation-induced cardiovascular dysfunction using human induced pluripotent stem cell (iPSC)-derived engineered heart tissues (EHTs) exposed to protracted γ-ray irradiation. The investigation of pathophysiological changes in this model may provide insights and guide the development of countermeasures. As a proof-of-principle for the application of this model in drug development, we also tested the protective effect of a mitochondrial-specific antioxidant, MitoTempo, on irradiated EHTs.

2023-09-05 | GSE242108 | GEO

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