32 / 40
31
Khawla Al-Ali
Department of Pharmacology
College of Medicine & Health Sciences
Dissertation
Title
Effects of Exercise and Pharmacological Intervention on Electromechanical Function of the
Heart in the Goto-Kakizaki Type 2 Diabetic Rat
Faculty Advisor
Professor Frank Christopher Howarth
Defense Date
16 June 2015
Abstract
Type 2 diabetes mellitus (T2DM) accounts for more than 90% of cases of diabetes mellitus. Cardiovascular diseases
are the major causes of morbidity and mortality in diabetic patients. A variety of diastolic and sys-tolic dysfunctions
have been reported. The severity of the abnormalities depends on the patients’ age and diabetes duration. The
aim of the study was to investigate the age-dependent, exercise and drug interven-tion on electromechanical
function of the heart in the Goto-Kakizaki (GK) type 2 diabetic rat. mRNA expres-sion was assessed in ventricular
muscle with real-time RT-PCR. Ventricular myocytes shortening, intracellu-lar Ca2+ transport and L-type Ca2+ current
were measured with video edge detection, fluorescence pho-tometry and whole cell patch clamp techniques,
respectively. In vivo biotelemetry was used to measure the electrocardiogram (ECG). In young GK (8-10 weeks) rat,
mRNA expression of Atp1a3, Cacna1h, Scn1b, Hcn2 were up-regulated and Slc9a1, Hcn4, Kcna2/4, Kcnj2 were down-
regulated. Amplitude of ventricular myo-cyte shortening and intracellular Ca2+ transient were unaltered, time to
peak shortening was prolonged and time to half decay of the Ca2+ transient was shortened in GK myocytes. Physical
exercise is well established as a valuable form of non-pharmacological therapy. Experiments were performed in
GK and control (10-11 months) following 2-3 months of treadmill exercise training. Expression of mRNA encoding
Tpm2, Gja4, Atp1b1, Cacna1g, Cacnb2, Hcn2, Kcna3 and Kcne1 were up-regulated and Gja1, Kcnj2 and Kcnk3
were down-regulated in hearts of sedentary GK rats compared to sedentary controls. Gja1, Cav3 and Kcnk3 were
up-regulated and Hcn2 was down-regulated in hearts of exercise trained GK compared to sedentary GK controls.
Amplitude of ventricular myocyte shortening, Ca2+ transients and L-type Ca2+ current were not significantly altered.
The effects of the anti-diabetic drug Pioglitazone (PIO) on ventricular myocyte shorten-ing and Ca2+ transport in
addition to ECG were also investigated. PIO (0.1-10) μM reduced the amplitude of shortening in ventricular myocytes
from GK and control rats. PIO reduced the amplitude of the Ca2+ transi-ent and modest reductions in L-type Ca2+
current in GK and control myocytes. Heart rate in GK rats was reduced. Although PIO reduced blood glucose in GK
rats it had little effect on heart ECG.
Research Relevance and Potential Impact
Diabetes mellitus is a serious global and national health problem and cardiovascular complications are the major cause of morbidity and mortality
in diabetic patients. Type 2 diabetes mellitus accounts for more than 90% of cases of diabetes and cardiovascular complications are the major
cause of morbidity and mortality in diabetic patients. Experiments performed in this research project have provided further clarification of the
cellular and subcellular basis of electromechanical dysfunction and the effects of exercise and drug intervention in type 2 diabetic heart. It is hoped
that this mechanistic understanding will help to facilitate the development of new treatment strategies for this disease.
Relevant Publications
• Salem KA, Adrian TE, Qureshi MA, Parekh K, Oz M, Howarth FC. Shortening and intracellular Ca2+ in ventricular myocytes and expression of genes
encoding cardiac muscle proteins in early onset type 2 diabetic Goto-Kakizaki rats. Exp Physiol. 2012 Dec; 97 (12):1281-91.
• Salem KA, Qureshi MA, Sydorenko V, Parekh K, Jayaprakash P, Iqbal T, Singh J, Oz M, Adrian TE, Howarth FC. (2012). Effects of exercise training on
excitation-contraction coupling and related mRNA expression in hearts of Goto-Kakizaki type 2 diabetic rats. Mol Cell Biochem.
2013 Aug; 380 (1-2): 83-96.
• Salem KA, Jacobson M, Shafiullah M, Oz M, Adeghate E, Howarth FC. Effects of pioglitazone on electrical conduction in the Goto-Kakizaki type
2 diabetic rat heart (Accepted in JCERC)
Career Aspirations
My aspirations are to acquire a PhD degree in Medical Sciences (Pharmacology track) and then pursue a research
and academic career. In the long term I would like to heighten awareness of the importance of research in our
community.