Cardiac Physiology Research Group

  Research Areas


            Cardiac muscle plays a crucial role in generating pressure in the cardiac chamber and controlling the amount of blood ejected from the heart.  As the highest cause of mortality rate in the whole world population, search for prevention and treatment of heart disease is the most excitement and dedication.  Thus, the going on research project in our laboratory has been mainly focused on understanding the role of sex hormones on physiological function as well as pathological intervention of the heart.



Female Sex Hormones & Cardiac Function
            A lower heart disease incidence in young women than that of age-matched men indicates the influence of gender difference in cardiac function.  Disappearance of this cardiac advantage after menopause thus suggests the cardio-protective effect of female sex hormones.  The evidence has led us to a long series of experimental investigations using ovariectomized rat as the model of study to demonstrate many effects of female sex hormone deprivation including:

  • 1. a decreased maximum cardiac myofilament Ca2+ ATPase activity.
  • 2. an increased cardiac myofilament Ca2+ sensitivity.
  • 3. a shift of myosin heavy chain toward more b-isoform.
  • 4. upregulation of cardiac b1-adrenergic receptors.
  • 5. a decreased amplitude of intracellular Ca2+ transients with a prolonged Ca2+ decay time.
  • 6. a decreased peak shortening with prolonged relaxation of the cardiac myocyte.
  • 7. decreases in maximum SR Ca2+ uptake and maximum SERCA activity.
  • 8. an increase in the SERCA Ca2+ sensitivity.
  • 9. downregulation of SERCA2a protein.
  • 10. a decreased phosphorylation level of phospholamban at theronine-17 site.
  • 11. an increased cardiac NHE1 activity.
Female Sex Hormones & Heart Disease Challenge
            Cardio-protective roles of female sex hormones have been elucidated by challenging with pathological insults like diabetes or angiotensin II-induced hypertension.  Our previous results and going on experiments show interactive actions of female sex hormones and diabetes or angiotensin II on cardiac functions in the following aspect:
  • 1. no synergistic interaction of ovarian sex hormone deficiency and diabetes on maximum cardiac myofilament Ca2+ ATPase activity.
  • 2. cardiac myofilament Ca2+ hypersensitivity after ovarian sex hormones deprivation still existes under diabetic complication.
  • 3. the shift in myosin heavy chain isoforms in ovariectomized rat heart is not the only mechanism underlying the reduction of maximum cardiac myofilament Ca2+ ATPase activity.
  • 4. the presence of female sex hormones increases myocardial stiffness and cardiac collagen content in diabetic rat.
  • 5. female sex hormones prevent the change in length-dependent myofilament Ca2+ sensitivity induced by diabetes.
  • 6. female sex hormones have no effect on myocardial stiffness under chronic angiotensin-II induction.
Male Sex Hormones & Cardiac Function
            Despite an indication of gender difference in cardiac function from the lower heart disease incidence in young women than that of age-matched men, a higher prevalence of cardiac dysfunction is still observed in men who have low plasma testosterone level.  On the other hand, the athlete who receives over dose of anabolic steroid such as testosterone for a long period of time would develop pathological hypertrophy of the heart with a potential of cardiac sudden death.  It is therefore interesting to investigate the regulatory role of male sex hormones on cardiac function in both aspects of hormone lacking and overdose.  We have demonstrated preliminary results concerning effects of male sex hormone deprivation using castrated rat model to include
  • 1. a decreased maximum cardiac myofilament Ca2+ ATPase activity.
  • 2. no change in cardiac myofilament Ca2+ sensitivity.
  • 3. a shift of myosin heavy chain toward more b-isoform.
  • 4. a decreased maximum SERCA activity with downregulation of SERCA2a protein.
  • 5. a Ca2+ hypersensitivity of SERCA.
            The pharmacological effect of male sex hormones on cardiac function has also been investigated.  Results from both time-and dose-dependent studies reveals that high dose of testosterone induces:
  • 1. cardiac hypertrophy with neither time- nor dose-dependence.
  • 2. a decrease in maximum force contraction in a time dependent manner.
  • 3. an increase in myocardial stiffness without time- and dose-dependence.
  • 4. bi-phasic changes in SERCA activity and SERCA2a expression in a dose-dependent manner.
  • 5. neither change in NCX activity nor protein expression.     

Female Sex Hormones & Exercise Training on Cardiac Function

            Though female sex hormones exert many beneficial outcomes to the heart, the use of hormone replacement therapy in postmenopausal women still gives rise to a risk of developing breast cancer.  We are then also interested in finding feasible alternatives to prevent cardiac dysfunction especially after menopausal period.  Our approach of introducing exercise training at moderate intensity to the ovariectomized rat clearly demonstrates a cardio-preventive outcome as expected.

            Figure shows the known regulatory targets for sex hormones reported from our studies including: 1) myofilament Ca2+ activation, 2) Ca2+-induced Ca2+ release process, 3) SR Ca2+ uptake activity, 4) NHE and NCX, 5) b1-adrenergic activity, 6) heat shock protein, and 7) extracellular matrix.   
  
Members in the Research Group
Staff:
             1. Assoc. Prof. Dr. Jonggonnee  Wattanapermpool
            2. Dr. Tepmanas  Bupha-Intr  

Students:
           1. Ms. Prapawadee  Pilompol
           2. Ms. Namthip Witayavanitkul
           3. Mr. Munthana  Wadethaisong
           4. Ms. Warunya  Woranush
           5. Ms. Sulaksana Pandit


Research Grants:
In the past 15 years, our group has received funding from 3 major sources.
           1. Thailand Research Fund
           2. The Commission of Higher Education
           3. Mahidol University

Publications :

1. Bupha-Intr., YW Oo, and J Wattanapermpool.  Increased myocardial stiffness with maintenance of length-dependent calcium activation by female sex hormones in diabetic rats.  Am. J. Physiol. Haert Circ Physiol. 300:H000-H000, 2011.
2.Bupha-Intr T., J Laosiripisan, and J Wattanapermpool.  Moderate intensity of regular exercise improves cardiac SR Ca2+ uptake activity in ovariec-tomized rats.  J Appl Physiol. 107:1105-1112, 2009.
3.Thawornkaiwong A., J Pantharanontaga, and J Wattanapermpool.  Hypersensitivity of myofilament response to Ca2+ in association with maladaptation of estrogen-deficient heart under diabetes complication.  Am. J. Physiol. Regul. Integr Comp. Physiol.  292: R844-851, 2007.
4. Bupha-Intr T., J. Wattanapermpool, JR Pena, BM Wolska, and RJ Solaro.  Myofilament response to Ca2+ and Na+/H+ exchanger activity in sex hormone related protection of cardiac myocytes from deactivation in hypercapnic acidosis.  Am. J. Physiol. Regul. Integr Comp. Physiol.  292: R837-843, 2007.
5. Bupha-Intr T. and J. Wattanapermpool.  Reguratory role of ovarian sex hormones in the calcium uptake activity of cardiac sarcoplasmic reticulum.  Am. J. Physiol. Haert Circ Physiol.  291:1101-1108, 2006.
6. Bupha-Intr T. and J. Wattanapermpool.  Cardioprotective effects of exercise training on myofilament calcium activation in ovariectomized rats.  J. Appl. Physiol.  96: 1755-1760, 2004.
7. Thawornkaiwong, A., S. Preawnim, and J. Wattanapermpool.  Upregulation of cardiac b1-adrenergic receptors in ovariectomized rat hearts.  Life Sciences 72: 1813-1824, 2003.   
8. Wattanapermpool, J., T Riabroy, and S. Preawnim.   Estrogen supplement prevents the calcium hypersensitivity of cardiac myofilaments in ovariectomized rats.  Life Sciences 66: 533-543, 2000.
9. Wattanapermpool, J. and P.J. Reiser.  Differential effects of ovariectomy on calcium activation of cardiac and soleus myofilaments.  Am. J. Physiol. 277: H467-473, 1999.
10. Wattanapermpool, J.  Changes in calcium responsiveness of cardiac myofilament activation in ovariectomized rats.  Life Sciences 63: 955-964, 1998.
11. Wattanapermpool, J., X. Guo, and R.J. Solaro.  The unique amino-terminal peptide of cardiac troponin I regulates myofibrillar activity only when it is phosphorylated.  J. Mol. Cell. Cardiol.  27:1383-1391, 1995.
12. Wattanapermpool, J., P.J. Reiser, and R.J. Solaro.  Troponin I isoforms and differential effects of acidic pH on soleus and cardiac myofilaments.  Am. J. Physiol. Cell  268(Cell Physiol. 37):C323-330, 1995.
13. Guo, X.,  J. Wattanapermpool,  K.A. Palmiter, A.M. Murphy, and R.J. Solaro.  Mutagenesis of cardiac troponin I: role of the unique NH2-teminal peptide in myofilament activation.  J. Biol. Chem.  269:15210-15216, 1994.
14. Koysooko, R., C. Bunyagidj, J. Wattanapermpool, and P. Chaichao.  HPLC determination of curcuminoids (from Curcumar longa) in biological fluids and its application.  Siriraj Hosp.  Gaz.  41:481-487, 1989.
15. Koysooko, R., P. Varavudhi, T. Pinthong, and J. Wattanapermpool.  Development of Zingiber cassumunar for asthmatic treatment: pharmacokinetics in animals.  J. Sci. Soc. Thailand 14:197-208, 1988.
16. Koysooko, R., T. Pinthong, and J. Wattanapermpool.   High performance liquid chromatographic determination of active constituent of Zingiber cassumunar in plasma.   Mahidol Univ. J. Pharm. Sci.  14:53-61, 1987.
17. Tuchinda, M., R. Koysooko, S. Habanananda, J. Wattanapermpool, and N. Arunyanark.  Relationship between theophylline concentration in serum and saliva of Thai asthmatic children.  Siriraj Hosp. Gaz. 39:245-252, 1987.
18. Koysooko, R., M. Tuchinda, S. Habanananda, T. Pinthong, J. Wattana-permpool, and S. Geadsomnuig.  Pharmacokinetics of oral theophylline in Thai asthmatic children.  Asian Pacific J. Allergy Immunol. 5:179-185, 1987.
19. Krishnamra, N., L. Limlomwonge, S. Subrungruang, and J.  Wattana-permpool.  Ethanol and bile calcium secretion in the rat.  J. Sci. Soc. Thailand.  12:97-109, 1986.