Cardiovascular disease culminates in a syndrome, congestive heart failure (CHF), in which the heart in unableto pump a sufficient quantity of blood to meet the metabolic needs of the individual. The factors that precipitateCHF and drive its progression are the topics of this research program. The proposed research challenges theexisting dogmas that the initiation and progression of CHF is caused by weakening of myocyte contractility andthat the adult heart is incapable of generating new myocytes. The working hypothesis of this research programis that a progressive reduction in the number of ventricular myocytes, rather than abnormalities in myocytefunction, is the primary factor that initiates and causes progression of heart failure. Specific hypotheses arethat myocyte death is induced by persistent increases in myocyte Ca2+ and that myocyte death can be offset bynew myocyte formation, to slow or reverse CHF progression. To test these ideas we have generated atransgenic mouse with cardiac specific, inducible expression of a subunit (CaV1.2p2a) of the L-type Ca2+channel, the major Ca2+ influx pathway in cardiac myocytes. Activation of CaV1.2(32a expression leads toincreased myocyte Ca2+ influx, Ca2+ transients and contractility which initially culminates in increasedventricular performance. However, after a few months these mice have increased myocyte death, cardiachypertrophy, ventricular and atrial dilation and reduced cardiac pump function. Interestingly, myocytes still haveincreased contractility. Preliminary studies also show that activation of the adrenergic signaling pathways,which also increase myocyte contractility, is involved in the initiation and progression of cardiac dysfunction inCaV1.2p2a mice. We have also recently shown that the normal heart has the capacity to generate newmyocyte during periods of physiological and pathological growth.
The specific aims of the proposed studies are1) To determine if persistent increases in Ca2+ influx through the L-type Ca2+ channel induces CHF by causingincreased myocyte death (via apoptosis and necrosis); 2) To determine if increased myocyte death induces anincrease in new myocyte formation which slows the rate of myocyte loss and provides a mechanism for cardiacregeneration if the factors causing myocyte death (CaV1.2p2a expression) are eliminated; and 3) To determineif activation of Pradrenergic receptors in CaV1.2(32a mice exacerbates myocyte death and if activation of p2-adrenergic receptors blunts myocyte death and enhances new myocyte formation. We will also explore the roleof myocyte death and new myocyte formation in the other models systems to be studied within this PPG.Support for our hypotheses will identify novel targets for CHF therapy and will change the thinking from currentapproaches that seek to increase myocyte force generation to those that seek to reduce myocyte death andpromote myocyte regeneration.
Showing the most recent 10 out of 163 publications
