Abstract
BackgroundPrior studies in animal models showed that increased cardiac expression of TRIB3 has a pathogenic role in inducing left ventricular mass (LVM). Whether alterations in TRIB3 expression or function have a pathogenic role in inducing LVM increase also in humans is still unsettled. In order to address this issue, we took advantage of a nonsynonymous TRIB3 Q84R polymorphism (rs2295490), a gain-of-function amino acid substitution impairing insulin signalling, and action in primary human endothelial cells which has been associated with insulin resistance, and early vascular atherosclerosis.MethodsSNP rs2295490 was genotyped in 2426 White adults in whom LVM index (LVMI) was assessed by validated echocardiography-derived measures.ResultsAfter adjusting for age and sex, LVMI progressively and significantly increased from 108 to 113, to 125 g/m2 in Q84Q, Q84R, and R84R individuals, respectively (Q84R vs. Q84Q, P = 0.03; R84R vs. Q84Q, P < 0.0001). The association between LVMI and the Q84R and R84R genotype remained significant after adjusting for blood pressure, smoking habit, fasting glucose levels, glucose tolerance status, anti-hypertensive treatments, and lipid-lowering therapy (Q84R vs. Q84Q, P = 0.01; R84R vs. Q84Q, P < 0.0001).ConclusionsWe found that the gain-of-function TRIB3 Q84R variant is significantly associated with left ventricular mass in a large sample of White nondiabetic individual of European ancestry.
Highlights
Prior studies in animal models showed that increased cardiac expression of tribbles homologue 3 (TRIB3) has a pathogenic role in inducing left ventricular mass (LVM)
There is evidence that altered expression of negative regulators of Protein kinase B (Akt) expression and activity such as phosphatase and tensin homologue (PTEN) [24], protein tyrosine phosphatase 1B (PTP1B) [25], the PH domain leucine-rich repeat protein phosphatase (PHLPP) [26], and tribbles homologue 3 (TRIB3) [27] may have a causative role in impairing the insulin signalling pathway. Amongst these Akt inhibitors, TRIB3 is a plausible candidate for linking molecular insulin resistance to LVM increase for the following reasons: (a) a rat model of type 2 diabetes induced by a combination of high-fat diet and low-dose streptozotocin exhibits insulin resistance, cardiac hypertrophy, and increased cardiac expression of TRIB3, as compared with control rats [28]; (b) silencing of TRIB3 in these diabetic rats restores Akt activity, reduces the phosphorylation of extracellular signal–regulated kinase 1/2, improves insulin resistance, and attenuates myocardial hypertrophy [28]; (c) dietary supplementation with Zn in db/db type 2 diabetic mice increases expression of the antioxidant metallothionein (MT), which results in reduction in TRIB3 expression accompanied by increased Akt2 activity, and protection from diabetes-induced cardiac structural and functional changes including LVM increase [29]
Subjects were excluded if they had diabetes mellitus, defined as fasting plasma glucose > 126 mg/dl or 2-h post-load plasma glucose > 200 mg/dl, current treatment with glucose-lowering agents or self-reported history of a previous diagnosis, end-stage renal disease (ESRD), chronic gastrointestinal diseases, liver cirrhosis, acute or chronic pancreatitis, acute or chronic infections, history of malignant or autoimmune diseases, history of alcohol or drug abuse, positivity for antibodies to hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg), and treatment with drugs known to influence glucose tolerance, such as steroids and estroprogestins employed for hormonal contraception or replacement treatment
Summary
Prior studies in animal models showed that increased cardiac expression of TRIB3 has a pathogenic role in inducing left ventricular mass (LVM). There is evidence that altered expression of negative regulators of Akt expression and activity such as phosphatase and tensin homologue (PTEN) [24], protein tyrosine phosphatase 1B (PTP1B) [25], the PH domain leucine-rich repeat protein phosphatase (PHLPP) [26], and tribbles homologue 3 (TRIB3) [27] may have a causative role in impairing the insulin signalling pathway Amongst these Akt inhibitors, TRIB3 is a plausible candidate for linking molecular insulin resistance to LVM increase for the following reasons: (a) a rat model of type 2 diabetes induced by a combination of high-fat diet and low-dose streptozotocin exhibits insulin resistance, cardiac hypertrophy, and increased cardiac expression of TRIB3, as compared with control rats [28]; (b) silencing of TRIB3 in these diabetic rats restores Akt activity, reduces the phosphorylation of extracellular signal–regulated kinase 1/2, improves insulin resistance, and attenuates myocardial hypertrophy [28]; (c) dietary supplementation with Zn in db/db type 2 diabetic mice increases expression of the antioxidant metallothionein (MT), which results in reduction in TRIB3 expression accompanied by increased Akt activity, and protection from diabetes-induced cardiac structural and functional changes including LVM increase [29].
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