Mechanisms and Functional Consequences of Cardiac Remodeling: Role of Myocardial Rac1 and Vascular Profilin1 Genes

Cardiovascular diseases remain the main cause of death in the Western world, with heart failure representing the highest increasing subclass over the past decade. A prosperity of data has confirmed the role of myocardial human Rac1 in the development of cardiac remodeling and heart failure in both animal and human patients. However, nothing is known about the effects of nonmammalian Rac protein on the mammalian heart. In an exciting discovery, we showed in chapter 2 of this thesis that a cardiac-specific and constitutively active mutant of a corn Rac gene, Zea mays RacD (ZmRacD) was able to act as an activator of oxidative burst in-vivo and resulted in cardiac hypertrophy with aging. These results indicate the remarkable functional and structural conservation of Rho/Rac proteins in both plant and animal kingdoms during evolution in-vivo and show that the ZmRacD mouse model is a valuable model that can relate changes induced by endogenous Rac. While physiological versus pathological hypertrophy can be obviously distinguished by numerous qualitative and quantitative parameters, the signaling mechanisms inducing the critical transition from compensated hypertrophy to decompensated heart failure remain poorly understood. In chapter 3, we took advantage of two cardiac models; a model of physiologic cardiac hypertrophy and another one of cardiac dilation that were developed after thyroxin (T4) administration to wild-type (WT) and ZmRacD transgenic mice, respectively to investigate the role of Rac-induced signaling in this transition process. Our data demonstrate that T4-induced ZmRacD is a novel mouse model of dilated cardiomyopathy that shares many characteristics with the human disease phenotype. We also showed that Rac-mediated superoxide (O2.-) generation, cardiomyocyte apoptosis and myocardial fibrosis seem to play a pivotal role in the transition from cardiac hypertrophy to cardiac dilation and failure. Furthermore, development of cardiac hypertrophy following T4 treatment is well recognized. However, the role of Rac1 in inducing this cardiac phenotype was unknown. In chapter 4, we provided the first mechanistic evidence for the partial involvement of Rac1 activation in T4-induced cardiomyocyte hypertrophy. We also revealed a putative role for Rac1 in T4-induced hypertension and showed that T4-induced cardiac hypertrophy and associated cardiac dysfunction are either not or partially dependent on hemodynamic changes. Finally, hypertension is a major health problem and a main risk factor for cardiovascular diseases including left ventricular (LV) hypertrophy. Previously, we have shown that profilin-1 overexpression in the blood vessel medial layer of transgenic mice favoring F-actin induces stress fiber formation and plays an important role in vascular hypertrophy by inducing internal mechanical stress, leading to vascular remodeling and hypertension by the time the profilin-1 mice were 6-month old. Mild hypertension clinically can only lead to LV hypertrophy and pathological conditions after prolonged sustenance. However, neither cardiac effects nor contractile functional measurements have ever been examined in profilin-1 mouse hearts at such later stages of age. In chapter 5, we showed that old profilin-1 mice exhibited mild LV hypertrophy and we also provided the first functional evidence that a significant contractile dysfunction in profilin-1 mice exists at both the whole heart and cardiac tissue levels.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Molecular, Cellular and Developmental Biology

Grantor dc:publisher

The Ohio State University

Year dc:date

2013

Author dc:creator

• Elnakish, Mohammad T.

Contributors dc:contributor

• Janssen, Paul

• Molecular Biology
• Pharmacology
• Physiology

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=osu1363694358

OAI identifier oai:identifier

oai:etd.ohiolink.edu:osu1363694358