C2. Alpha 11 integrin a mediator of myofibrolastic transformation and fibrosis formation in the failing heart.

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C8. Cardioprotective benefits of combined treatment with glucagon-like peptide-1 receptor agonist and sodium glucose transporter 2 inhibitor in mice

Dorrin Zarrin Khat, Abdul Momen, Muhammad A. Siraj, Sina Hadipour-Lakmehsari, Mark J. Chandy, Mansoor Husain

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C8. Cardioprotective benefits of combined treatment with glucagon-like peptide-1 receptor agonist and sodium glucose transporter 2 inhibitor in mice

Dorrin Zarrin Khat, Abdul Momen, Muhammad A. Siraj, Sina Hadipour-Lakmehsari, Mark J. Chandy, Mansoor Husain

Posted by on January 1, 2018

Poster_session_2 Cardio

Poster Session 2 - C2

1Patrick Meagher BSc (Honours), 2Robert Civitarese MSc, 3Jean-Francios Desjardin MSc, 4Golam Kabir Msc MD, 1,2,3,4,5Kim Connelly MBBS PhD

1) Keenan Research Centre for Biomedical Science, St. Michael’s Hospital; Department of Physiology, University of Toronto, Toronto ON, Canada 2) Keenan Research Centre for Biomedical Science, St. Michael’s Hospital; Institute of Medical Science, University of Toronto, Toronto ON, Canada 3) Keenan Research Center for Biomedical Science, St. Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada 4) Faculty of Medicine, University of Toronto, Toronto ON, Canada 5) Division of Cardiology, St. Michael’s Hospital, Toronto ON, Canada

Heart failure (HF) is a significant clinical problem that is increasing worldwide. The latest statistics from the American Heart Association would suggest the number of people affect by heart failure has increased to 6.5million people (2012-2014)(1). Many patients who suffer from heart failure don’t see improvements from current therapeutic treatments. In particular, patients who are observed to have a preserved ejection fraction are a group of patients who see no proven clinical benefit from the currently available therapeutics(2, 3). Many treatments for heart failure focus on improving the function of two main cell types within the heart either cardiomyocytes or endothelial cells but not fibroblasts. Fibroblast transformation to myofibroblast leading to adverse cardiac remodeling in particular of the extracellular matrix is a significant contributor to the progression of HF(4, 5). Cardiac fibroblasts account for ~10% of all cells within the heart(6). Importantly, fibroblast are connected to the ECM by integrin’s which act to connect fibroblast to the ECM and conduct mechanical signals to the cell(7). Integrin’s exist in both alpha and beta subunits and there are twenty-four subtypes. Further, with collagens being the most abundant ECM proteins collagen Integrin’s have become an interest in heart failure for their role in fibrosis formation. Integrin Alpha 11 is seen to be expressed on cardiac fibroblasts(8). Alpha 11 has been demonstrated to promote the development of a fibrotic interstitium in diabetic cardiomyopathy with the action dependent on TGF- 2 and Smad 3 signaling(8). Thus, to investigate the role of alpha 11 we employed transverse aortic constriction (TAC) to induce pressure overload which, resulted in cardiomyocyte hypertrophy and increased interstitial fibrosis along with impaired cardiac function. Further, the adverse remodelling events were associated with increases in the mRNA expression from qt-PCR and protein expression from western blots of alpha 11 integrin. Additionally, western blots of cardiac biopsy samples demonstrated upregulation of alpha 11 protein expression in HF. To further investigate the role of alpha 11 in fibrosis formation and myofibroblastic transformation we have employed a knock out model of alpha 11. Preliminary data does in fact suggest that loss of alpha 11 does in fact inhibits cardiomyocytes hypertrophy in a pressure overload model. This work demonstrates an association between alpha 11 integrin signalling and adverse remodeling in response to HF. Current data indicates a role for alpha 11 in signalling fibroblast to myofibroblast transformation however, further evidence is needed to demonstrate the importance of alpha 11 and its mechanism of action.

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