Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension

Chirinos, Julio A.; Sardana, Mayank; Syed, Amer Ahmed; Koppula, Maheshwara Reddy; Varakantam, Swapna; Vasim, Izzah; Oldland, Harold G.; Phan, Timothy S.; Drummen, Nadja E.A.; Vermeer, Cees; Townsend, Raymond R.; Akers, Scott; Wei, Wen Bin; Lakatta, Edward G.; Федорова, О. В.

doi:10.1016/j.jash.2018.06.018

Cited by 21 publications

(16 citation statements)

References 34 publications

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“…9 For this reason, previous studies have suggested that MGP influences vascular stiffness through its role in preventing calcification. 20,57 It was interesting, therefore, that ucMGP levels were associated with vascular stiffness in the absence of an association with detectable vascular calcification. However, our study is limited in that the human and mouse imaging techniques may not be able to detect microcalcifications.…”

Section: Discussionmentioning

confidence: 99%

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction

Malhotra

Nicholson

Wang

et al. 2022

ATVB

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Objective: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction. MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp +/− mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident heart failure with preserved ejection fraction. Aortic PWV was increased in older, but not young, female Mgp +/− mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. Conclusions: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future heart failure with preserved ejection fraction in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in heart failure with preserved ejection fraction.

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Section: Discussionmentioning

confidence: 99%

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction

Malhotra

Nicholson

Wang

et al. 2022

ATVB

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“…69 In this regard, aldosterone is associated with high levels of inactive matrix Gla protein, a vitamin K-dependent protein that inhibits arterial calcification. 70 Spironolactone could also reduce aortic stiffness in stage 3 CKD through the reduction of vascular fibrosis. 71 However, its use in more advanced stages of CKD should be carefully evaluated because of the risk of hyperkalaemia.…”

Section: Antihypertensive Drugsmentioning

confidence: 99%

Arterial Stiffness in the Heart Disease of CKD

Zanoli

Lentini

Briet

et al. 2019

JASN

153

130

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CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

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“…Vitamin K status in co-morbidities associated with poor Coronavirus disease 2019 outcomes dp-ucMGP levels are elevated in various diseases that are associated with elastic fibre calcification and degradation such as diabetes (35) , hypertension (36) , CVD (37) , chronic kidney disease (35,38) and obesity (39) . It is possible that reduced vitamin K intake increases the risk of developing these conditions (40) .…”

Section: Vitamin K Metabolism In Coronavirus Disease 2019mentioning

confidence: 99%

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019

et al. 2020

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Coronavirus disease 2019 (Covid-19), caused by SARS-CoV-2, exerts far-reaching effects on public health and socioeconomic welfare. The majority of infected individuals have mild to moderate symptoms but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in activation of both pro- and anticlotting factors in the liver, and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2 induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in prevention and treatment of severe Covid-19.

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Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension

Cited by 21 publications

References 34 publications

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction

Arterial Stiffness in the Heart Disease of CKD

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019

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