Matrix GIa Protein, Large Artery Stiffness, and the Risk of Heart Failure With Preserved Ejection Fraction

Chirinos, Julio A.

doi:10.1161/atvbaha.121.317206

Cited by 2 publications

(2 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As such, it is critical to define drivers of MAC such as MGP, which in some clinical studies in humans has been associated with heart failure and MAC (65). Impairment in MGP activation, which would phenocopy genetic deletion, is linked to a higher risk of heart failure and peripheral artery disease due to excessive pulsatile afterloads on the left ventricle that reduce coronary artery perfusion pressure during diastole (66,67). As the mice that lack MGP are prone to aortic rupture or heart failure, we speculate that rapamycin's effect on the mice's lifespan may be due to rapamycin acting on the cardiac tissues.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification

Behzadi,

Cuevas,

Crane

et al. 2024

Preprint

View full text Add to dashboard Cite

Peripheral artery disease (PAD) is the narrowing of the arteries that carry blood to the lower extremities. PAD has been traditionally associated with atherosclerosis. However, recent studies have found that medial arterial calcification (MAC) is the primary cause of chronic limb ischemia below the knee. MAC involves calcification of the elastin fibers surrounding smooth muscle cells (SMCs) in arteries. Matrix GLA Protein (MGP) binds circulating calcium and inhibits vascular calcification.Mgp-/-mice develop severe MAC and die within 8 weeks of birth due to aortic rupture or heart failure. We previously discovered a rare genetic disease Arterial Calcification due to Deficiency in CD73 (ACDC) in which patients present with extensive MAC in their lower extremity arteries. Using a patient-specific induced pluripotent stem cell model we found that rapamycin inhibited calcification. Here we investigated whether rapamycin could reduce MAC in vivo usingMgp-/-mice as a model.Mgp+/+andMgp-/-mice received 5mg/kg rapamycin or vehicle. Calcification content was assessed via microCT, and vascular morphology and extracellular matrix content assessed histologically. Immunostaining and western blot analysis were used to examine SMC phenotypes and cellular functions. Rapamycin prolongedMgp-/-mice lifespan, decreased mineral density in the arteries, and increased smooth muscle actin protein levels, however, calcification volume, vessel morphology, SMC proliferation, and autophagy flux were all unchanged. These findings suggest that rapamycin’s effects in theMgp-/-mouse are independent of the vascular phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification

Behzadi,

Cuevas,

Crane

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Higher circulating inactive MGP is also associated with higher risk of heart failure and peripheral artery disease ( Dalmeijer et al, 2013 ; Malhotra et al, 2022 ). Excessive arterial stiffness due to impaired MGP activation increases the pulsatile afterloads for the left ventricle and reduces coronary artery perfusion pressure during diastole, leading to heart failure ( Chirinos, 2022 ). These results imply that activated MGP protects against vascular calcification and resulting cardiovascular diseases.…”

Section: Inhibitory Roles Of Mgp In Vascular Calcificationmentioning

confidence: 99%

The vascular protective effect of matrix Gla protein during kidney injury

Kida

Yamaguchi²

2022

Front. Mol. Med

View full text Add to dashboard Cite

Matrix Gla protein (MGP) is a small secreted protein and requires vitamin K dependent γ-carboxylation for its function. MGP has been identified as a local inhibitor of vascular calcification because MGP-deficient mice die due to severe arterial calcification and resulting arterial rupture. Clinical trials revealed that reduction in active MGP predicts poor prognosis in patients due to cardiovascular complications. However, recent studies showed that MGP controls angiogenesis during development. MGP-deficient mice demonstrated abnormal hypervascularization and arteriovenous malformations in kidneys and other organs. This abnormal angiogenesis is largely caused by excessive expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR2). However, only a few studies have investigated the roles of MGP in tissue injury. We observed mesangial cell proliferation and mild interstitial fibrosis in addition to increased capillaries in kidneys of MGP-null mice even without injury. We also created a mouse model with kidney injury and found that kidney damage greatly increases MGP expression in peritubular capillary endothelial cells and tubular epithelial cells. Finally, our study showed that impairment of MGP expression aggravates peritubular capillary rarefaction and accumulation of collagen-producing myofibroblasts following kidney injury. Peritubular capillary damage induces capillary loss as well as trans-differentiation of vascular pericytes into myofibroblasts. These results indicate that MGP has the vascular protective effect in the injured kidney. Clinical trials have already started to test the efficacy of MGP activation to repair vascular calcification in patients with chronic kidney diseases. In this “Hypothesis and Theory” article, we discuss possible mechanisms by which MGP protects against vascular damage during tissue injury based on our experimental results and previous results from other research groups.

show abstract

Matrix GIa Protein, Large Artery Stiffness, and the Risk of Heart Failure With Preserved Ejection Fraction

Cited by 2 publications

References 15 publications

Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification

Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification

The vascular protective effect of matrix Gla protein during kidney injury

Contact Info

Product

Resources

About