Haptoglobin Genotype and Its Role in Diabetic Cardiovascular Disease

Costacou, Tina; Levy, Andrew P.

doi:10.1007/s12265-012-9361-z

Cited by 49 publications

(52 citation statements)

References 104 publications

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“…In this context, it is important to note that the genetics of haptoglobin [41] has been shown to influence the consequences of IPH, particularly in diabetic patients. The remarkable studies by the group of AP Levy identified the H1-1 allele of haptoglobin polymorphism as a protective allele against coronary artery disease in diabetic patients, associated with an enhanced clearance of hemoglobin/haptoglobin complexes( [42] for review). Conversely, the H2-2 allele provided a worse prognosis for carotid plaques in epidemiologic study [43], associated with a more elevated expression of Haem Oxygenase1 in endarteriectomized plaques.…”

Section: Mechanisms Of Neovascularization and Intraplaque Haemorrhagementioning

confidence: 99%

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

et al. 2014

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Section: Mechanisms Of Neovascularization and Intraplaque Haemorrhagementioning

confidence: 99%

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

et al. 2014

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“…Recently, studies in the general population showed a lower prevalence of the Haptoglobin (Hp) 2 allele among individuals with cerebrovascular disease (5-7), a surprising observation given consistent prospective findings of an increased cardiovascular and end-stage renal disease (8) risk associated with the Hp 2 allele in diabetes.…”

Section: Introductionmentioning

confidence: 98%

Haptoglobin genotype and cerebrovascular disease incidence in type 1 diabetes

Costacou

Secrest

Ferrell

et al. 2014

Diabetes and Vascular Disease Research

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Objective We prospectively evaluated the Haptoglobin (Hp)-stroke association in type 1 diabetes and hypothesized that despite increasing the risk for coronary artery disease, the presence of the Hp 2 allele would lower stroke incidence. Methods Participants from the Epidemiology of Diabetes Complications study without prevalent stroke and Hp available were evaluated (n=607; mean age, 27.6 and duration, 19.3 years). Results During 22 years of follow-up, stroke incidence did not differ by Hp genotype (p=0.49). Restricting analyses to those diagnosed with diabetes ≥1965 (13% mortality versus 40% in the <1965 cohort) to diminish potential survival bias, the adjusted HR for Hp 1-1 was 3.08 (95% CI=0.81-11.77, p=0.10). Further stratifying by hypertension prevalence, an increased stroke incidence was observed with Hp 1-1 only in those with hypertension (HR=7.03, 95% CI=1.42-34.89, p=0.02). Conclusions Despite the protective effect against vascular diabetes complications, a borderline increased risk for stroke was observed with Hp 1-1 in type 1 diabetes. This mixed Hp effect on cardiovascular risk by outcome studied merits further investigation and cautions against the universal application of preventive therapies across all Hp genotypes.

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“…Hp has been studied extensively both at the genetic and biochemical level in the context of diabetes and its macrovascular complications (7, 8). Andrew Levy and colleagues demonstrated that among the three Hp genotypes; Hp 1-1, Hp 2-1, and Hp 2-2, the Hp 2-2 genotype is associated with increased cardiovascular disease in diabetes (7, 8). In humans, the potential for increased oxidative damage caused by the Hp 2-2–hemoglobin complex is attributed to elevated levels of Hp 2-2 in the circulation (9).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E ^−/− Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function

Mehta

Grijalva

Hama

et al. 2016

ATVB

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Objective We previously reported that Hemopexin (Hx), a heme scavenger, is significantly increased and associated with proinflammatory HDL under atherogenic conditions. Although it is established that Hx together with macrophages plays a role in mitigating oxidative damage, the role of Hx in the development of atherosclerosis is unknown. Approach and Results We used Hx and apoE double knockout mice (HxE−/−) to determine the role of Hx in the development of atherosclerosis. HxE−/− mice had significantly more free heme, ROS, and proinflammatory HDL in their circulation, when compared to control apoE−/− mice. Atherosclerotic plaque area (apoE−/− = 9.72 ± 2.5 x104 μm2 and HxE−/− = 27.23 ± 3.6 x104 μm2) and macrophage infiltration (apoE−/− = 38.8 ± 5.8 x103 um2 μm2 and HxE−/− = 103.4 ± 17.8 x103 μm2) in the aortic sinus were significantly higher in the HxE−/− mice. Atherosclerotic lesions in the aortas were significantly higher in the HxE−/− mice compared to apoE−/− mice. Analysis of polarization revealed that macrophages from HxE−/− mice were more M1-like. Ex vivo studies demonstrated that HxE−/− macrophage cholesterol efflux capacity was significantly reduced when compared to apoE−/− mice. Injection of human Hx (hHx) into HxE−/− mice reduced circulating heme levels and hHx pretreatment of naïve bone marrow cells ex vivo resulted in a shift from M1-like to M2-like macrophages. Conclusion We conclude that Hx plays a novel protective role in alleviating heme induced oxidative stress, improving inflammatory properties of HDL, macrophage phenotype and function, and inhibiting the development of atherosclerosis in apoE−/− mice.

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Haptoglobin Genotype and Its Role in Diabetic Cardiovascular Disease

Cited by 49 publications

References 104 publications

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

Haptoglobin genotype and cerebrovascular disease incidence in type 1 diabetes

Apolipoprotein E ^−/− Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function

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Haptoglobin Genotype and Its Role in Diabetic Cardiovascular Disease

Cited by 49 publications

References 104 publications

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

Pathology of human plaque vulnerability: Mechanisms and consequences of intraplaque haemorrhages

Haptoglobin genotype and cerebrovascular disease incidence in type 1 diabetes

Apolipoprotein E −/− Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function

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Apolipoprotein E ^−/− Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function