Date on Master's Thesis/Doctoral Dissertation
Physiology and Biophysics
Physiology and Biophysics, PhD
Heart--Diseases--Treatment; Myocardial infarction--Prevention; Linolenic acids--Therapeutic use
According to the CDC, the most common type of heart disease is coronary artery disease, which frequently leads to myocardial infarction (MI). Therapeutic approaches to lessen the resulting cardiovascular injury associated with MI are limited. Recently, the management paradigm for cardiac injury has entered the molecular era and microRNAs (miRNAs) have been shown to act as negative regulators of gene expression by inhibiting mRNA translation and/or stimulating mRNA degradation. A single miRNA can modulate physiological or disease phenotypes by regulating whole functional systems. Importantly, miRNAs can regulate cardiac function, thereby modulating heart muscle contraction, heart growth and morphogenesis. MicroRNA-499 (miRNA-499) is a cardiac-specific miRNA that when elevated causes cardiomyocyte hypertrophy, in turn preventing cardiac dysfunction during MI. Previous studies revealed that the combination treatment of conjugated linoleic acid (cLA) and nitrite preserved cardiovascular function in mice. Therefore, we hypothesized that cLA and nitrite may regulate miRNA-499, thus providing cardiac protection during MI. To test this hypothesis, 12-week old mice were treated with cLA (10 mg/kg/d-via osmotic mini-pump) or cLA and nitrite (50 ppm-drinking water) 3 days prior to MI (ligation of the left anterior descending artery). Echocardiography and pressure-volume (PV)-loop analysis revealed that cLA and nitrite-treated MI mice had improved heart function (10 days following MI) compared to untreated MI mice. Treatment with cLA and nitrite significantly induced levels of miRNA-499 compared to untreated MI mice. In addition, treatment with cLA and nitrite abolished MI-induced protein expression of p53 and dynamin-related protein-1 (DRP-1). Moreover, the antioxidant enzyme expression of heme oxygenase-1 (HO-1) was elevated in MI mice treated with cLA and nitrite compared to untreated MI mice. Confocal imaging on heart tissue confirmed expression the levels of HO-1 and p53. Taken together, these results suggest that therapeutic treatment with cLA and nitrite may provide significant protection during MI through regulation of both cardiac specific miRNA-499 and upregulation of phase 2 antioxidant enzyme expression. As we demonstrate in our study cLA and nitrite co administration decreased apoptosis though the HO-1 and/or miRNA-499 pathway. To investigate more deeply the role of HO-1 and/or miRNA-499 in apoptosis, we used HO-1 Tg and HO-1 KO mice. Our data supported the hypothesis that HO-1 regulates miRNA-499 levels and thus decreases apoptosis after MI. As others and we have demonstrated before, MI is known to cause cardiomyocyte ischemia, in turn, leading to cardiomyocyte apoptosis [1, 2]. The current study extends previous findings by demonstrating that ischemia causes an increased ratio of Bax/Bcl-2 following MI in non-treated C57 mice and in HO-1 KO mice. Our data demonstrate that in HO-1 KO mice the expression of miRNA-499 is not detectable. Overall, these data reveal links among p53, HO-1, miRNA-499, and Drp1 with regard to regulation of the apoptotic programed cell death in the heart. Taken together, these results suggest that therapeutic treatment with cLA and nitrite may provide cardiac protection during MI through the regulation of induction of cardiac specific HO-1 expression, which further regulated cardiac specific miRNA-499.
Kelm, Natia Qipshidze, "Combination treatment with conjugated linoleic acid and nitrite protects against myocaridal infarction." (2015). Electronic Theses and Dissertations. Paper 2227.