A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification

Goettsch, Claudia; Hutcheson, Joshua D.; Hagita, Sumihiko; Rogers, Maximillian A.; Creager, Michael; Pham, Tan; Choi, Jung Hyun; Mlynarchik, Andrew K.; Pieper, Brett; Kjølby, Mads; Aikawa, Masanori; Aïkawa, Elena

doi:10.1016/j.atherosclerosis.2016.06.011

Cited by 99 publications

(79 citation statements)

References 17 publications

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“…The pro-inflammatory effect of PCSK9 has been shown in different experimental models [27][28][29]. The inhibitory effect of PCSK9 on vascular calcification was also suggested in several basic experiments [30,31]. In addition, clinical evidence supported a linkage between PCSK9 and chemokine and vascular calcification in previous studies [24,32].…”

Section: Discussionmentioning

confidence: 80%

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Hwang

Kim

et al. 2020

JCM

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for the prevention of cardiovascular (CV) events. However, the clinical significance of circulating PCSK9 is unclear in hemodialysis (HD) patients. A total of 353 HD patients were prospectively enrolled from June 2016 to August 2019 in a K-cohort. Plasma PCSK9 level was measured at the time of study enrollment. The primary endpoint was defined as a composite of CV event and death. Plasma PCSK9 level was positively correlated with total cholesterol level in patients with statin treatment. Multivariate linear regression analysis revealed that baseline serum glucose, albumin, total cholesterol, and statin treatment were independent determinants of circulating PCSK9 levels. Cumulative rates of composite and CV events were significantly higher in patients with tertile 3 PCSK9 (p = 0.017 and p = 0.010, respectively). In multivariate Cox-regression analysis, PCSK9 tertile 3 was associated with a 1.97-fold risk of composite events (95% CI, 1.13–3.45), and it was associated with a 2.31-fold risk of CV events (95% CI, 1.17–4.59). In conclusion, a higher circulating PCSK9 level was independently associated with incident CV events and death in HD patients. These results suggest the importance of future studies regarding the effect of PCSK9 inhibition.

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Section: Discussionmentioning

confidence: 80%

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Hwang

Kim

et al. 2020

JCM

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“…Mice were given a single tail vein injection of murine PCSK9 gain-of-function adeno-associated virus (AAV; which mimics Ldlr -deficiency pathology in mice), fed an atherogenic diet for twenty weeks, and then analyzed in a similar manner to that which we and others have previously reported 42–44 . Drp1 +/− male mice ( N =5) did not have significantly altered body weight, serum triglycerides, or total cholesterol, compared to Drp1 +/+ male siblings (Figure 6A).…”

Section: Resultsmentioning

confidence: 99%

Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress

Rogers

Maldonado

Hutcheson

et al. 2017

Circulation Research

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Rationale Mitochondrial changes occur during cell differentiation and cardiovascular disease. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical problem with high unmet needs. Objective To examine the effects of osteogenic promoting conditions on DRP1, and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells (SMCs) increased DRP1 expression. DRP1 inhibition in human SMCs undergoing osteogenic differentiation attenuated matrix mineralization, cytoskeletal rearrangement, mitochondrial dysfunction, and reduced type 1 collagen secretion and alkaline phosphatase activity. DRP1 protein was observed in calcified human aortic valves, and DRP1 RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for Drp1 deletion did not exhibit altered vascular pathology in a PCSK9 gain-of-function atherosclerosis model. However, when mineralization was induced via oxidative stress, DRP1 inhibition attenuated mouse and human SMC calcification. Femur bone density was unchanged in mice heterozygous for Drp1 deletion, and DRP1 inhibition attenuated oxidative stress-mediated dysfunction in human bone osteoblasts. Conclusions We demonstrate a new function of DRP1 in regulating collagen secretion and cardiovascular calcification, a novel area of exploration for the potential development of new therapies to modify cellular fibrocalcific response in cardiovascular diseases. Our data also support a role of mitochondrial dynamics in regulating oxidative stress-mediated arterial calcium accrual and bone loss.

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“…Overexpression of PCSK9 results in an increased degradation of LDLR [173]. When mice are injected a gain of function PCSK9 adeno-associated virus vector (AAV), they develop increased cholesterol levels, atherosclerotic lesions and aortic calcification [174].…”

Section: Lipoprotein Systemmentioning

confidence: 99%

Research Models for Studying Vascular Calcification

Herrmann

Babic

Tölle

et al. 2020

IJMS

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Calcification of the vessel wall contributes to high cardiovascular morbidity and mortality. Vascular calcification (VC) is a systemic disease with multifaceted contributing and inhibiting factors in an actively regulated process. The exact underlying mechanisms are not fully elucidated and reliable treatment options are lacking. Due to the complex pathophysiology, various research models exist evaluating different aspects of VC. This review aims to give an overview of the cell and animal models used so far to study the molecular processes of VC. Here, in vitro cell culture models of different origins, ex vivo settings using aortic tissue and various in vivo disease-induced animal models are summarized. They reflect different aspects and depict the (patho)physiologic mechanisms within the VC process.

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A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification

Abstract: Background-Studying atherosclerotic calcification in vivo requires mouse models with genetic

Cited by 99 publications

References 17 publications

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress

Research Models for Studying Vascular Calcification

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