Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 67 (12), 2695-2702

Insulin Resistance and Vulnerability to Cardiac Ischemia

Affiliations

Insulin Resistance and Vulnerability to Cardiac Ischemia

Tomas Jelenik et al. Diabetes.

Abstract

Hepatic and myocardial ectopic lipid deposition has been associated with insulin resistance (IR) and cardiovascular risk. Lipid overload promotes increased hepatic oxidative capacity, oxidative stress, and impaired mitochondrial efficiency, driving the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that higher lipid availability promotes ischemia-induced cardiac dysfunction and decreases myocardial mitochondrial efficiency. Mice with adipose tissue-specific overexpression of sterol element-binding protein 1c as model of lipid overload with combined NAFLD-IR and controls underwent reperfused acute myocardial infarcts (AMIs). Whereas indexes of left ventricle (LV) contraction were similar in both groups at baseline, NAFLD-IR showed severe myocardial dysfunction post-AMI, with prominent LV reshaping and increased end-diastolic and end-systolic volumes. Hearts of NAFLD-IR displayed hypertrophy, steatosis, and IR due to 18:1/18:1-diacylglycerol-mediated protein kinase Cε (PKCε) activation. Myocardial fatty acid-linked respiration and oxidative stress were increased, whereas mitochondrial efficiency was decreased. In humans, decreased myocardial mitochondrial efficiency of ventricle biopsies related to IR and troponin levels, a marker of impaired myocardial integrity. Taken together, increased lipid availability and IR favor susceptibility to ischemia-induced cardiac dysfunction. The diacylglycerol-PKCε pathway and reduced mitochondrial efficiency both caused by myocardial lipotoxicity may contribute to the impaired LV compensation of the noninfarcted region of the myocardium.

Trial registration: ClinicalTrials.gov NCT03386864.

Figures

Figure 1
Figure 1
NAFLD associates with cardiac hypertrophy and increased lipid accumulation but no edema or fibrosis in the heart of NAFLD-IR mice. A: The heart weight (n = 7–9 per group). B: The ratio of the heart weight to body weight (BW) (n = 7–9 per group). C: Capillary density expressed as number of capillaries per square millimeter (left panel), as assessed from the immunohistochemical staining of the frozen myocardial tissue sections with anti-CD31 monoclonal antibodies (representative photographs shown in the right panel) (n = 10 per group). D: Representative photographs of the frozen myocardial tissue sections after immunohistochemical staining with anti–wheat germ agglutinin antibodies as a marker of fibrosis. E: Water content in the whole heart assessed with desiccation method (n = 5 per group). F: Cardiac lipids measured by 1H-MRS in vivo (n = 8–10 per group). G: Representative photographs of the frozen myocardial tissue sections after immunohistochemical staining with anti–perilipin 2 antibodies as a marker of lipid droplets. H: Relative protein expression of perilipin 2 levels in the heart assessed with Western blots and normalized to total protein (TP) (n = 5 per group). All data are presented as mean ± SEM. **P < 0.01 and ***P < 0.001, Student t test. A.U., arbitrary units.
Figure 2
Figure 2
NAFLD-IR mice are characterized by decreased insulin sensitivity of the heart, paralleled by the induction of the diacylglycerol-PKCε pathway. A: Glucose infusion rate as an indicator of the whole-body insulin sensitivity was measured with hyperinsulinemic-euglycemic clamps (n = 5–7 per group). B and C: Relative protein expression of the Akt and membrane GLUT4 in the heart assessed with Western blots and normalized to total protein (TP) (n = 5 per group). D: Relative mRNA expression of Pdk4 in the heart assessed with quantitative RT-PCR (n = 5 per group). E and F: Total diacylglycerol (DAG) levels in the membrane fraction of the heart and their fatty acid composition (n = 6–7 per group). G: Relative protein expression of the membrane PKCε in the heart assessed with Western blots and normalized to TP (n = 5 per group). H and I: Total DAG levels in the cytosolic fraction of the heart and their fatty acid composition (n = 6–7 per group). J: Relative protein expression of the cytosolic PKCε in the heart assessed with Western blots and normalized to TP (n = 5 per group). All data are presented as mean ± SEM. *P < 0.05 and ***P < 0.001, Student t test. A.U., arbitrary units.
Figure 3
Figure 3
Cardiac morphology and function of NAFLD-IR mice at baseline and after AMI. A: Representative MRI with late gadolinium enhancement (LGE) showing the infarcted area (bright myocardium) on day 1 after AMI. B: Quantification of the infarction size on the day 1 post-AMI using LGE. C: Representative MRI of the end-diastole (upper panels) and end-systole (lower panels) hearts on day 14 post-AMI. D: LV mass. E: Heart rate. F: End-diastolic volume (EDV) of the LV. G: End-systolic volume (ESV) of the LV. H: The percent thickening of the LV wall with systole. I: Ejection fraction of the LV. All data are presented as mean ± SEM (n = 8–9 per group). *P < 0.05, **P < 0.01, and ***P < 0.001 between genotypes matched for time (multiple Student t test).
Figure 4
Figure 4
Mitochondrial respiration and oxidative stress in the heart of NAFLD-IR mice at baseline conditions and after AMI. A: Oxygen consumption linked to complex I (pyruvate and glutamate), complex II (succinate), and electron transfer flavoprotein complex (CETF; octanoyl-carnitine) at state 3 (adp) and state 4o (oligomycin [omy]) respiration in isolated heart mitochondria (n = 7–8 per group). B: H2O2 emission from complex III (antimycin) and dose-response curves of succinate-stimulated H2O2 emission in isolated heart mitochondria (n = 8 per group). C: Phosphate-to-oxygen (P/O) ratio, an indicator of the mitochondrial efficiency, assessed by dividing the moles of ADP phosphorylated to ATP by the moles of atomic oxygen consumed by isolated heart mitochondria (n = 5 per group). D: Oxygen consumption linked to complex I + II (pyruvate, glutamate, and succinate) and CETF (octanoyl-carnitine) at state 3 (adp) respiration was assessed in permeabilized left heart ventricles at baseline and 28 days after AMI (n = 5–10 per group). E: H2O2 emission from complex III (antimycin) was assessed in permeabilized LV at baseline and 28 days post-AMI (n = 5–10 per group). F: sORP and antioxidant capacity assessed in serum from mice 28 days post-AMI (n = 7–8 per group). G: Catalase activity in the serum of mice at baseline and 28 days post-AMI (n = 5–10). H: Concentrations of TBARS in the serum of mice at baseline and 28 days post-AMI (n = 5–10 per group). All data are presented as mean ± SEM. *P < 0.05, Student t test or two-way ANOVA.

Similar articles

See all similar articles

Cited by 6 articles

See all "Cited by" articles

References

    1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595–602 - PubMed
    1. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015;62(Suppl.):S47–S64 - PubMed
    1. Koliaki C, Szendroedi J, Kaul K, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 2015;21:739–746 - PubMed
    1. Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol 2017;14:32–42 - PubMed
    1. Goldberg IJ, Trent CM, Schulze PC. Lipid metabolism and toxicity in the heart. Cell Metab 2012;15:805–812 - PMC - PubMed

Publication types

MeSH terms

Associated data

Feedback