Jankowski M.,Cardiovascular Biochemistry Laboratory |
Jankowski M.,University of Montreal |
Broderick T.L.,Midwestern University |
Gutkowska J.,Cardiovascular Biochemistry Laboratory |
Gutkowska J.,University of Montreal
BMC Endocrine Disorders | Year: 2016
Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion with OT into an ischemic or failing heart has the potential to elicit a variety of cardioprotective effects. OT treatment attenuates cardiomyocyte (CMs) death induced by ischemia-reperfusion by activating pro-survival pathways within injured CMs in vivo and in isolated cells. OT treatment reduces cardiac apoptosis, fibrosis, and hypertrophy. The OT/OT receptor (OTR) system is downregulated in the db/db mouse model of type 2 diabetes which develops genetic diabetic cardiomyopathy (DC) similar to human disease. We have shown that chronic OT treatment prevents the development of DC in the db/db mouse. In addition, OT stimulates glucose uptake in both cardiac stem cells and CMs, and increases cell resistance to diabetic conditions. OT may help replace lost CMs by stimulating the in situ differentiation of cardiac stem cells into functional mature CMs. Lastly, adult stem cells amenable for transplantation such as MSCs could be preconditioned with OT ex vivo and implanted into the injured heart to aid in tissue regeneration through direct differentiation, secretion of protective and cardiomyogenic factors and/or their fusion with injured CMs. © 2016 The Author(s).
Plante E.,Cardiovascular Biochemistry Laboratory |
Plante E.,University of Montreal |
Menaouar A.,Cardiovascular Biochemistry Laboratory |
Danalache B.A.,Cardiovascular Biochemistry Laboratory |
And 6 more authors.
Diabetologia | Year: 2014
Aims/hypothesis: Obesity and diabetes increase the risk of developing cardiovascular diseases and heart failure. These metabolic disorders are generally reflected by natriuretic peptide system deficiency. Since brain natriuretic peptide (BNP) is known to influence metabolism and cardioprotection, we investigated the effect of chronic exogenous BNP treatment on adverse myocardial consequences related to obesity and diabetes. Methods: Ten-week-old C57BL/KsJ-db/db obese diabetic mice (db/db) and their lean control littermates (db/+) were treated with BNP (0.6 μg kg-1 h-1) or saline for 12 weeks (n∈=∈10/group). Serial blood and tomography analysis were performed. Cardiac function was determined by echocardiography, and biochemical and histological heart and fat analyses were also performed. Results: BNP treatment resulted in an average increase in plasma BNP levels of 70 pg/ml. An improvement in the metabolic profile of db/db mice was observed, including a reduction in fat content, increased insulin sensitivity, improved glucose tolerance and lower blood glucose, despite increased food intake. db/db mice receiving saline displayed both early systolic and diastolic dysfunction, whereas these functional changes were prevented by BNP treatment. The cardioprotective effects of BNP were attributed to the inhibition of cardiomyocyte apoptosis, myocardial fibrosis, cardiac hypertrophy and the AGE-receptor for AGE (RAGE) system as well as normalisation of cardiac AMP-activated protein kinase and endothelial nitric oxide synthase activities. Conclusions/interpretation: Our results indicate that chronic BNP treatment at low dose improves the metabolic profile and prevents the development of myocardial dysfunction in db/db mice. © 2014 Springer-Verlag Berlin Heidelberg.
Gonzalez-Reyes A.,Cardiovascular Biochemistry Laboratory |
Gonzalez-Reyes A.,McGill University |
Menaouar A.,Cardiovascular Biochemistry Laboratory |
Yip D.,Cardiovascular Biochemistry Laboratory |
And 8 more authors.
Molecular and Cellular Endocrinology | Year: 2015
Oxytocin (OT) stimulates cardioprotection. Here we investigated heart-derived H9c2 cells in simulated ischemia-reperfusion (I-R) experiments in order to examine the mechanism of OT protection. I-R was induced in an anoxic chamber for 2 hours and followed by 2 h of reperfusion. In comparison to normoxia, I-R resulted in decrease of formazan production by H9c2 cells to 63.5 ± 1.7% (MTT assay) and in enhanced apoptosis from 1.7 ± 0.3% to 2.8 ± 0.4% (Tunel test). Using these assays it was observed that treatment with OT (1-500 nM) exerted significant protection during I-R, especially when OT was added at the time of ischemia or reperfusion. Using the CM-H2DCFDA probe we found that OT triggers a short-lived burst in reactive oxygen species (ROS) production in cells but reduces ROS production evoked by I-R. In cells treated with OT, Western-blot revealed the phosphorylation of Akt (Thr 308, p-Akt), eNOS and ERK 1/2. Microscopy showed translocation of p-Akt and eNOS into the nuclear and perinuclear area and NO production in cells treated with OT. The OT-induced protection against I-R was abrogated by an OT antagonist, the Pi3K inhibitor Wortmannin, the cGMP-dependent protein kinase (PKG) inhibitor, KT5823, as well as soluble guanylate cyclase (GC) inhibitor, ODQ, and particulate GC antagonist, A71915. In conditions of I-R, the cells with siRNA-mediated reduction in OT receptor (OTR) expression responded to OT treatment by enhanced apoptosis.In conclusion, the OTR protected H9c2 cells against I-R, especially if activated at the onset of ischemia or reperfusion. The OTR-transduced signals include pro-survival kinases, such as Akt and PKG. © 2015 Elsevier Ireland Ltd.