Dominant role of CACNA1D exon mutations for blood pressure regulation

Wang, Huan; Zhu, Jie; Cheng, Lan; Mao, Gaowei; Chen, Hong; Wu, Xiaoying; Hong, Huiwu; Wang, Canwang; Lin, Pengcheng; Chen, Jie; Maboh, Rene Nfornah; Chen, Hui

doi:10.1097/hjh.0000000000003085

Cited by 7 publications

(6 citation statements)

References 41 publications

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“…26,27 Follow-up studies identified 7 CACNA1D exon locus mutations that correlated with hypertension. 28 Wang et al 29 selected 3 of these mutations and utilized CRISPR-Cas9 technology to generate Sprague-Dawley rats carrying mutations of the CACNA1D gene. Higher BP was observed in rats with double-site mutants versus those with single-site mutant and in rats with single-site mutations versus wild-type rats.…”

Section: Discussionmentioning

confidence: 99%

CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals

Stanton,

Heydarpour,

Williams

et al. 2023

Hypertension

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BACKGROUND: Disease-causing mutations in CACNA1D gene occur in aldosterone-producing adenomas and familial hyperaldosteronism. We determined whether single nucleotide polymorphisms in CACNA1D gene associate with higher aldosterone resulting in salt sensitivity of blood pressure (BP) and increased BP in men and women. METHODS: Data were obtained from the HyperPATH (International Hypertension Pathotypes) cohort, where participants completed a cross-over intervention of liberal and restricted sodium diets. Multi-Ethnic Genotyping Array identified 104 CACNA1D single nucleotide polymorphisms that met quality control. Single nucleotide polymorphism is rs7612148 strongly associated with systolic BP and was selected for study in 521 Whites in 3 scenarios ([1] hypertensives; [2] normotensives; [3] total population=hypertensives+normotensives) using multivariate regression analysis. RESULTS: In the total population and hypertensives, but not normotensives, risk allele carriers (CC, GC), as compared with nonrisk allele homozygotes (GG), exhibited higher salt sensitivity of BP and, on liberal sodium diet, higher systolic BP, lower baseline and angiotensin II–stimulated aldosterone, and lower plasma renin activity. On restricted sodium diet, BP was similar across genotypes, suggesting sodium restriction corrected/neutralized the genotype effect on BP. Because increased aldosterone did not seem to drive the increased salt sensitivity of BP and increased BP on liberal sodium diet, we assessed renal plasma flow. Renal plasma flow increase from restricted to liberal sodium diets was blunted in risk allele homozygotes in the total population and in hypertensives. A replication study in another cohort HyperPATH B (International Hypertension Pathotypes Cohort B) confirmed BP-genotype associations. CONCLUSIONS: CACNA1D rs7612148 risk allele associated with increased BP and salt sensitivity of BP, likely due to an impaired ability to increase renal plasma flow in response to a liberal sodium diet and not to excess aldosterone.

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Section: Discussionmentioning

confidence: 99%

CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals

Stanton,

Heydarpour,

Williams

et al. 2023

Hypertension

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“…This gene encodes the α1 subunit of the Cav1.3 L‐type calcium channel that regulates (in part) intracellular Ca 2+ stability. Wang et al 42 . generated, with Crispr‐Cas9 technology, a series of rats with CACNA1D variants.…”

Section: Calcineurin In Vascular Smooth Musclementioning

confidence: 99%

“…This gene encodes the α1 subunit of the Cav1.3 L-type calcium channel that regulates (in part) intracellular Ca 2+ stability. Wang et al 42 generated, with Crispr-Cas9 technology, a series of rats with CACNA1D variants. In mutant rats, Cav1.3 protein expression and calcineurin phosphatase activity in vascular smooth muscle cells were increased.…”

Section: Calcineurin In Vascular Smooth Musclementioning

confidence: 99%

Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses

Luft

2024

Acta Physiologica

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AimTo place the consequences of calcineurin inhibition in a cardiovascular context.MethodsLiterature review coupled with personal encounters.ResultsCalcineurin is a calcium‐binding and calmodulin‐binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium‐dependent, calmodulin‐stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research.ConclusionCalcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.

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“…The CACNA1D gene, which encodes the α1 subunit of the Cav1.3 L-type calcium channel, effectively regulates intracellular Ca 2+ stability. Several recent clinical studies have shown that CACNA1D polymorphisms are associated with hypertension [ 73 , 74 , 75 ].…”

Section: Molecular Link Between Cardiovascular Diseases and Prostate ...mentioning

confidence: 99%

Cardiovascular Complications in Patients with Prostate Cancer: Potential Molecular Connections

Kakkat

Pramanik

Singh

et al. 2023

IJMS

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Cardiovascular diseases (CVDs) and complications are often seen in patients with prostate cancer (PCa) and affect their clinical management. Despite acceptable safety profiles and patient compliance, androgen deprivation therapy (ADT), the mainstay of PCa treatment and chemotherapy, has increased cardiovascular risks and metabolic syndromes in patients. A growing body of evidence also suggests that patients with pre-existing cardiovascular conditions show an increased incidence of PCa and present with fatal forms of the disease. Therefore, it is possible that a molecular link exists between the two diseases, which has not yet been unraveled. This article provides insight into the connection between PCa and CVDs. In this context, we present our findings linking PCa progression with patients’ cardiovascular health by performing a comprehensive gene expression study, gene set enrichment (GSEA) and biological pathway analysis using publicly available data extracted from patients with advanced metastatic PCa. We also discuss the common androgen deprivation strategies and CVDs most frequently reported in PCa patients and present evidence from various clinical trials that suggest that therapy induces CVD in PCa patients.

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Dominant role of CACNA1D exon mutations for blood pressure regulation

Cited by 7 publications

References 41 publications

CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals

CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals

Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses

Cardiovascular Complications in Patients with Prostate Cancer: Potential Molecular Connections

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