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TIMP3 interplays with apelin to regulate cardiovascular metabolism in hypercholesterolemic mice.

Stöhr R, Kappel BA, Carnevale D, Cavalera M, Mavilio M, Arisi I, Fardella V, Cifelli G, Casagrande V, Rizza S, Cattaneo A, Mauriello A, Menghini R, Lembo G, Federici M - Mol Metab (2015)

Bottom Line: ApoE(-/-)TIMP3(-/-) revealed decreased lifespan.Metabolomics analysis revealed an increase in circulating markers of oxidative stress with a reduction in long chain fatty acids.Apelin is a regulator of fatty acid oxidation, and we found a reduction in the levels of enzymes involved in fatty acid oxidation in the left ventricle of ApoE(-/-)TIMP3(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy ; Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

ABSTRACT

Objective: Tissue inhibitor of metalloproteinase 3 (TIMP3) is an extracellular matrix (ECM) bound protein, which has been shown to be downregulated in human subjects and experimental models with cardiometabolic disorders, including type 2 diabetes mellitus, hypertension and atherosclerosis. The aim of this study was to investigate the effects of TIMP3 on cardiac energy homeostasis during increased metabolic stress conditions.

Methods: ApoE(-/-)TIMP3(-/-) and ApoE(-/-) mice on a C57BL/6 background were subjected to telemetric ECG analysis and experimental myocardial infarction as models of cardiac stress induction. We used Western blot, qRT-PCR, histology, metabolomics, RNA-sequencing and in vivo phenotypical analysis to investigate the molecular mechanisms of altered cardiac energy metabolism.

Results: ApoE(-/-)TIMP3(-/-) revealed decreased lifespan. Telemetric ECG analysis showed increased arrhythmic episodes, and experimental myocardial infarction by left anterior descending artery (LAD) ligation resulted in increased peri-operative mortality together with increased scar formation, ventricular dilatation and a reduction of cardiac function after 4 weeks in the few survivors. Hearts of ApoE(-/-)TIMP3(-/-) exhibited accumulation of neutral lipids when fed a chow diet, which was exacerbated by a high fat, high cholesterol diet. Metabolomics analysis revealed an increase in circulating markers of oxidative stress with a reduction in long chain fatty acids. Using whole heart mRNA sequencing, we identified apelin as a putative modulator of these metabolic defects. Apelin is a regulator of fatty acid oxidation, and we found a reduction in the levels of enzymes involved in fatty acid oxidation in the left ventricle of ApoE(-/-)TIMP3(-/-) mice. Injection of apelin restored the hitherto identified metabolic defects of lipid oxidation.

Conclusion: TIMP3 regulates lipid metabolism as well as oxidative stress response via apelin. These findings therefore suggest that TIMP3 maintains metabolic flexibility in the heart, particularly during episodes of increased cardiac stress.

No MeSH data available.


Related in: MedlinePlus

Metabolic characterization of ApoE−/−TIMP3−/− mice reveals impaired lipid oxidation. A) Analysis of fasting glucose levels reveals significant reduction in ApoE−/−TIMP3−/− mice (***p < 0.001, Student's t test, n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). B) Intraperitoneal Glucose Tolerance test shows no significant differences between the two groups (n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). C) Mild insulin resistance of ApoE−/−TIMP3−/− mice at the Insulin Tolerance Test (*p < 0.05, Student's t test, n = n = 4 for ApoE−/− and n = 5 for ApoE−/−TIMP3−/− per group). D) Indirect calorimetry of ApoE−/−TIMP3−/− compared to ApoE−/− mice during 12 consecutive hours of fasting conditions. Data show the interval from 8 to 12 h of fasting. RER was significantly increased and lipid oxidation significantly reduced in ApoE−/−TIMP3−/− mice (*p < 0.05, Student's t test, n = 3–4).
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fig3: Metabolic characterization of ApoE−/−TIMP3−/− mice reveals impaired lipid oxidation. A) Analysis of fasting glucose levels reveals significant reduction in ApoE−/−TIMP3−/− mice (***p < 0.001, Student's t test, n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). B) Intraperitoneal Glucose Tolerance test shows no significant differences between the two groups (n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). C) Mild insulin resistance of ApoE−/−TIMP3−/− mice at the Insulin Tolerance Test (*p < 0.05, Student's t test, n = n = 4 for ApoE−/− and n = 5 for ApoE−/−TIMP3−/− per group). D) Indirect calorimetry of ApoE−/−TIMP3−/− compared to ApoE−/− mice during 12 consecutive hours of fasting conditions. Data show the interval from 8 to 12 h of fasting. RER was significantly increased and lipid oxidation significantly reduced in ApoE−/−TIMP3−/− mice (*p < 0.05, Student's t test, n = 3–4).

Mentions: ApoE−/−TIMP3−/− mice further showed a complex metabolic phenotype characterized by a trend to lower fasting glucose, a normal Glucose Tolerance Test (GTT) coupled to mild insulin resistance during the Insulin Tolerance Test (*p < 0.05, ***p < 0.001, Student's t test, Figure 3A–C).


TIMP3 interplays with apelin to regulate cardiovascular metabolism in hypercholesterolemic mice.

Stöhr R, Kappel BA, Carnevale D, Cavalera M, Mavilio M, Arisi I, Fardella V, Cifelli G, Casagrande V, Rizza S, Cattaneo A, Mauriello A, Menghini R, Lembo G, Federici M - Mol Metab (2015)

Metabolic characterization of ApoE−/−TIMP3−/− mice reveals impaired lipid oxidation. A) Analysis of fasting glucose levels reveals significant reduction in ApoE−/−TIMP3−/− mice (***p < 0.001, Student's t test, n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). B) Intraperitoneal Glucose Tolerance test shows no significant differences between the two groups (n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). C) Mild insulin resistance of ApoE−/−TIMP3−/− mice at the Insulin Tolerance Test (*p < 0.05, Student's t test, n = n = 4 for ApoE−/− and n = 5 for ApoE−/−TIMP3−/− per group). D) Indirect calorimetry of ApoE−/−TIMP3−/− compared to ApoE−/− mice during 12 consecutive hours of fasting conditions. Data show the interval from 8 to 12 h of fasting. RER was significantly increased and lipid oxidation significantly reduced in ApoE−/−TIMP3−/− mice (*p < 0.05, Student's t test, n = 3–4).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4588459&req=5

fig3: Metabolic characterization of ApoE−/−TIMP3−/− mice reveals impaired lipid oxidation. A) Analysis of fasting glucose levels reveals significant reduction in ApoE−/−TIMP3−/− mice (***p < 0.001, Student's t test, n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). B) Intraperitoneal Glucose Tolerance test shows no significant differences between the two groups (n = 14 for ApoE−/− and n = 6 for ApoE−/−TIMP3−/− per group). C) Mild insulin resistance of ApoE−/−TIMP3−/− mice at the Insulin Tolerance Test (*p < 0.05, Student's t test, n = n = 4 for ApoE−/− and n = 5 for ApoE−/−TIMP3−/− per group). D) Indirect calorimetry of ApoE−/−TIMP3−/− compared to ApoE−/− mice during 12 consecutive hours of fasting conditions. Data show the interval from 8 to 12 h of fasting. RER was significantly increased and lipid oxidation significantly reduced in ApoE−/−TIMP3−/− mice (*p < 0.05, Student's t test, n = 3–4).
Mentions: ApoE−/−TIMP3−/− mice further showed a complex metabolic phenotype characterized by a trend to lower fasting glucose, a normal Glucose Tolerance Test (GTT) coupled to mild insulin resistance during the Insulin Tolerance Test (*p < 0.05, ***p < 0.001, Student's t test, Figure 3A–C).

Bottom Line: ApoE(-/-)TIMP3(-/-) revealed decreased lifespan.Metabolomics analysis revealed an increase in circulating markers of oxidative stress with a reduction in long chain fatty acids.Apelin is a regulator of fatty acid oxidation, and we found a reduction in the levels of enzymes involved in fatty acid oxidation in the left ventricle of ApoE(-/-)TIMP3(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy ; Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

ABSTRACT

Objective: Tissue inhibitor of metalloproteinase 3 (TIMP3) is an extracellular matrix (ECM) bound protein, which has been shown to be downregulated in human subjects and experimental models with cardiometabolic disorders, including type 2 diabetes mellitus, hypertension and atherosclerosis. The aim of this study was to investigate the effects of TIMP3 on cardiac energy homeostasis during increased metabolic stress conditions.

Methods: ApoE(-/-)TIMP3(-/-) and ApoE(-/-) mice on a C57BL/6 background were subjected to telemetric ECG analysis and experimental myocardial infarction as models of cardiac stress induction. We used Western blot, qRT-PCR, histology, metabolomics, RNA-sequencing and in vivo phenotypical analysis to investigate the molecular mechanisms of altered cardiac energy metabolism.

Results: ApoE(-/-)TIMP3(-/-) revealed decreased lifespan. Telemetric ECG analysis showed increased arrhythmic episodes, and experimental myocardial infarction by left anterior descending artery (LAD) ligation resulted in increased peri-operative mortality together with increased scar formation, ventricular dilatation and a reduction of cardiac function after 4 weeks in the few survivors. Hearts of ApoE(-/-)TIMP3(-/-) exhibited accumulation of neutral lipids when fed a chow diet, which was exacerbated by a high fat, high cholesterol diet. Metabolomics analysis revealed an increase in circulating markers of oxidative stress with a reduction in long chain fatty acids. Using whole heart mRNA sequencing, we identified apelin as a putative modulator of these metabolic defects. Apelin is a regulator of fatty acid oxidation, and we found a reduction in the levels of enzymes involved in fatty acid oxidation in the left ventricle of ApoE(-/-)TIMP3(-/-) mice. Injection of apelin restored the hitherto identified metabolic defects of lipid oxidation.

Conclusion: TIMP3 regulates lipid metabolism as well as oxidative stress response via apelin. These findings therefore suggest that TIMP3 maintains metabolic flexibility in the heart, particularly during episodes of increased cardiac stress.

No MeSH data available.


Related in: MedlinePlus