Scott Heximer

Research Synopsis

Keywords: Cardiac Fibrosis/ cardiac fibroblast activation/arrhythmogenesis/sinoatrial myocyte function/atrial myocyte function/ Heterotrimeric G-protein signaling/RGS protein function/

Detailed Description:  
Heart Failure is often associated with altered cardiac signaling and function within myocytes and supporting cells including fibroblasts.  Our work aims to understand cardiac signaling in normal and diseased states between all of the different cell types within the heart.  Two primary areas of focus for our group are currently: 1) understanding how altered heterotrimeric G-protein signaling can lead to altered cardiac function; and 2) characterizing how different subpopulations of cardiac-resident fibroblasts respond to altered signaling cues during the development of heart failure.

Cardiac Cell Signaling and Function in Experimental Models of Heart Disease:
Heterotrimeric G-protein signaling is involved in the regulation of important cardiac cell functions including inotropy and pacemaking within the sinoatrial node. Our work has shown that proper regulation of parasympathetic signals in the sinoatrial node requires the function of RGS proteins, a specialized family of heterotrimeric G-protein signaling inhibitors.  RGS4 knockout mice show profound sensitivity to parasympathetic activity at the level of heart rate control and susceptibility to atrial arrhythmias. Our recent work has been aimed at understanding the effect of altered RGS4 function on pacemaking and arrhythmogenesis in cardiac tissues.

Understanding Cardiac Fibroblast Function in Heart Disease Models:
Cardiac fibroblasts are a heterogenous population of cardiac-resident cells whose altered signaling and function contribute variably to both the pathogenesis and repair of hearts exposed to an injurious stimulus. Our work sets out to understand the various subpopulations of cardiac fibroblasts in the mouse (and human) heart with the aim of identifying populations of these cells that may serve as a pool of local reparative cells in the heart following cardiac injury.

METHODS USED

Cell and tissue culture models: Cardiac fibroblsts, cardiomyocytes, smooth muscle cells, endothelial cells, atrial tissue, perfused heart (Langendorf), sinoatrial node cells

Procedures: adenoviral-mediated  gene transfer into cells and tissues, aortic banding (LV pressure overload), behavioural tests, cAMP RIA, confocal microscopy, EEG, electrophysiology, fluorescence activated cell sorting, Fura-2 calcium imaging, gene expression analysis,  genetically-altered mouse models immunohistochemistry, inositol phosphate measurement, in-vitro electrophysiology, in-vivo electrophysiology, isolated atria preparation, isolated resistance vessel preparation, LAD ligation, mouse femoral artery injury, patch clamp, proteomics, pulmonary artery banding, radiotherapy, RIA, RT-PCR, single cell and bulk RNA-sequencing methods siRNA, vagotomy, vessel cannulation, voltage clamp, western blot.

EQUIPMENT USED

Amplifier (ADI BioLab), analytical balances, benchtop centrifuge, blood pressure telemetry units for mice (DSI), blotting apparatus, calcium imaging system (PTI), culture hood, culture incubators, dissecting microscope, ECG telemetry units for mice (DSI), fluorescence microscope, gel apparatus, infusion apparatus, microwave oven, Millar 1.4F solid state blood pressure catheters, mini vortexer, monochromator, stimulator, telemetry workstation (DSI), water baths.

PRESENT TRAINEES
Michael Dewar
Fahad Ehsan

PRESENT COLLABORATIONS

Within the Department of Physiology:
Steffen-Sebastian Bolz
Anthony Gramolini
Zhong-Ping Feng
Adria Giacca
Mansoor Husain
Mike Wheeler
Mark Friedberg

Outside the Department of Physiology:
Michelle Bendeck
Clinton Robbins
Slava Epelman
Craig Simmons
Boris Hinz
Bob Mecham (Washington University in St. Louis)

Committee member/officer of national/international scientific organizations:
Past President (2019-2021), Canadian Society for Atherosclerosis Thrombosis and Vascular Biology (CSATVB)

Recent Publications

1. Blaser MC, Wei K, Adams RLE, Zhou YQ, Caruso LL, Mirzaei Z, Lam AY, Tam RKK, Zhang H, Heximer SP, Henkelman RM, Simmons CA. Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice.    Circ Res. 2018 Feb 2;122(3):405-416.
2. Dingwell LS, Shikatani EA, Besla R, Levy AS, Dinh DD, Momen A, Zhang H, Afroze T, Chen MB, Chiu F, Simmons CA, Billia F, Gommerman JL, John R, Heximer S, Scholey JW, Bolz SS, Robbins CS, Husain M.B-Cell Deficiency Lowers Blood Pressure in Mice.    Hypertension. 2019 Mar;73(3):561-570.
3. Hadipour-Lakmehsari S, Driouchi A, Lee SH, Kuzmanov U, Callaghan NI, Heximer SP, Simmons CA, Yip CM, Gramolini AO. Nanoscale reorganization of sarcoplasmic reticulum in pressure-overload cardiac hypertrophy visualized by dSTORM. Sci Rep. 2019 May 27;9(1):7867
4. CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage. Lidington D, Fares JC, Uhl FE, Dinh DD, Kroetsch JT, Sauvé M, Malik FA, Matthes F, Vanherle L, Adel A, Momen A, Zhang H, Aschar-Sobbi R, Foltz WD, Wan H, Sumiyoshi M, Macdonald RL, Husain M, Backx PH, Heximer SP, Meissner A, Bolz SS. JACC Basic Transl Sci. 2019 Nov 27;4(8):940-958.
5. Experimental Subarachnoid Hemorrhage Drives Catecholamine-Dependent Cardiac and Peripheral Microvascular Dysfunction. Dinh DD, Lidington D, Kroetsch JT, Ng C, Zhang H, Nedospasov SA, Heximer SP, Bolz SS. Front Physiol. 2020 May 13;11:402.
6. RGS4 controls Gαi3-mediated regulation of Bcl-2 phosphorylation on TGN38-containing intracellular membranes. Bastin G, Dissanayake K, Langburt D, Tam ALC, Lee SH, Lachhar K, Heximer SP. J Cell Sci. 2020 Jun 24;133(12):jcs241034.
7. Resveratrol Inhibits Neointimal Growth after Arterial Injury in High-Fat-Fed Rodents: The Roles of SIRT1 and AMPK. Guo J, Pereira TJ, Mori Y, Gonzalez Medina M, Breen DM, Dalvi PS, Zhang H, McCole DF, McBurney MW, Heximer SP, Tsiani EL, Dolinsky VW, Giacca A. J Vasc Res. 2020;57(6):325-340.
8. Myocardial Infarction Induces Cardiac Fibroblast Transformation within Injured and Noninjured Regions of the Mouse Heart.  Shah H, Hacker A, Langburt D, Dewar M, McFadden MJ, Zhang H, Kuzmanov U, Zhou YQ, Hussain B, Ehsan F, Hinz B, Gramolini AO, Heximer SP. J Proteome Res. 2021 May 7;20(5):2867-2881.
9. RGS4-Deficiency Alters Intracellular Calcium and PKA-Mediated Control of Insulin Secretion in Glucose-Stimulated Beta Islets. Bastin G, Luu L, Batchuluun B, Mighiu A, Beadman S, Zhang H, He C, Al Rijjal D, Wheeler MB, Heximer SP. Biomedicines. 2021 Aug 13;9(8):1008.
10. Deletion of type VIII collagen reduces blood pressure, increases carotid artery functional distensibility and promotes elastin deposition. Mohabeer AL, Kroetsch JT, McFadden M, Khosraviani N, Broekelmann TJ, Hou G, Zhang H, Zhou YQ, Wang M, Gramolini AO, Mecham RP, Heximer SP, Bolz SS, Bendeck MP. Matrix Biol Plus. 2021 Sep 29;12:100085.