Name: PAULA LOPES RODRIGUES
Publication date: 07/11/2017
Advisor:
Name |
Role |
|---|---|
| EDUARDO HERTEL RIBEIRO | Advisor * |
| IVANITA STEFANON | Co-advisor * |
Examining board:
| Name |
Role |
|---|---|
| ANDRÉ SOARES LEOPOLDO | External Examiner * |
| DALTON VALENTIM VASSALLO | Internal Examiner * |
| EDUARDO HERTEL RIBEIRO | Advisor * |
| IVANITA STEFANON | Co advisor * |
| SUELY GOMES DE FIGUEIREDO | Internal Examiner * |
Summary: After an acute ischemic event, myocardial loss determines the appearance of mechanical dysfunction of the heart. Cardiac failure can be associated to a loss of energy metabolism due to a lower production of adenosine triphosphate and exacerbation of oxidative stress from cardiac mitochondrion accompanied by losses in the acyl linoleic chain of cardiolipin. The aim of the present study was to evaluate the effects of linoleic acid (LA) on cardiac contractility and mitochondrial function in two spatially distinct subpopulations: the subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) of rats followed myocardial infarction (MI). The first part of this study was designed to determine the LA dose able to improve cardiac and mitochondrial function in control rats. Wistar rats were divided into groups and received 0.1 mL i.m. from different doses of AL (5 mg / kg, 15 mg / kg and 50 mg / kg) or saline 0.9% for 15 days. No differences were found in the diastolic (DBP) and systolic (SBP) arterial pressures among the Sham and LA groups (SBP: Sham 102 ± 2; LA5: 92 ± 3; LA15: 102 ± 3; LA50: 104 ± 4 mmHg; DBP: Sham 64 ± 2, LA5: 57 ± 3, LA15: 66 ± 3, LA50: 71 ± 6 mmHg). The increase of left ventricular diastolic pressure (DP) promoted a greater increment in left ventricular isovolumic pressure (LVISP) in the LA treated groups (DP 15 mmHg: Sham 85,9 ± 4,8, LA15: 107,1 ± 7, LA50 : 135,8 ± 13,2 * mmHg, * p <0,05). The inotropic response to 2,5 mM Ca2+ was higher in the LA50 group (Sham 93,9 ± 5,3, LA50: 116,6 ± 5 * mmHg, * p <0,05). Mitochondrial function, using the substrate Glutamate + Malate (G + M), was increased in state 3 of oxidative phosphorylation in all LA-treated groups (Sham 124±16,6, LA5: 193±17 *, LA15: 138±19 *; LA50: 162±14 * nmol O / min / mg protein; * p <0.05). The treatment with LA decreased the probability of calcium-induced mitochondrial pore opening (Sham 49754±1185; LA5: 45369±1090 *; LA5: 46563±1026 *; LA50: 39851±5677 * nmol Ca 2 + / mg protein; * p <0,05). The calcium tolerance test was higher in the LA50 group (Sham: 0,895 + 0,009; AL50: 0,914±0,006 *; * p <0,05 after 640 s). Considering those results,in the second part of this study, we selected the dose 50 mg / kg of LA to to treat the MI rats during 15 days. MI was surgical induced by the occlusion of the left anterior descending coronary artery (MI) and the control animals submitted to sham surgery. The animals
were divided to receive, for 15 days 0.1 mL i.m. of NaCl (Sham and MI) or linoleic acid 50 mg / kg, Sham group (LA) and MI group (MILA). After this period, histological analyzes and evaluation of ventricular and left ventricular mitochondrial function were performed in addition to cardiac protein expression (SERCA-2a, PLB, PGC1α, NRF e PPARα). MI and MILA animals developed similar phenotypic changes, such as increased heart mass,increased deposition of cardiac fibrous tissue, and infarct size. However, LA partially prevented ventricular dysfunction after MI (LVISP Sham: 110 ± 15; MI: 52 ± 16 *; MILA: 88 ± 32 mmHg, * vs Sham; * p <0,05). In addition, LA prevented the cardiac mitochondrial dysfunction of the MI group represented by the reduction in the rate of oxidative phosphorylation with the substrates G + M (Respiratory Control Ratio (RCR) IFM Sham: 2,94±0,24; MI: 1,81±0,17*; MILA: 2,55±0,38,* vs Sham; p<0,05), piruvate + malate (RCR IFM Sham: 2,40±0,26; MI:1,97±0,2*; MILA: 2,35±0,5,* vs Sham;*p<0,05) in the IFM and SSM subpopulation; (Sham: 0,8 ± 0,1, MI: 1,2 ± 0,2 *, MILA: 0,9 ± 0,2, * vs Sham; p<0,05) and calcium retention capacity (IFM Sham: 50924 ± 6037; MI: 24541±4459*; MILA: 13064±13191*, * vs Sham; * p <0,05). The MI group showed dysfunction of the electron transport chain with decreased complexes III, IV and V in the mitochondrial IFM subpopulation,increased the complexes I, II, III and IV in SSM in the MILA group. LA treatment decreased expression of Uniporter and increase of cyclophilin in the MI group only in the IFM subpopulation. In conclusion, treatment with linoleic acid at a dose of 50 mg / kg for 15 days partially prevent the left ventricular dysfunction and improve the mitochondrial function of the SSM and IFM subpopulations after MI in rats.
