Regulation of mitochondrial dynamics is essential for cardiovascular disease (CVD) related issues like chronic heart failure (CHF). Up regulation of proteolytic activities such as calpains and matrix metallo-proteinases (MMP's) are found within the CHF model. Although calpains have been known to underline the degradative roles leading to cell death, the molecular mechanisms are unclear. Additionally, the mitochondrial aspects of myocyte death need much to be determined. Mitochondrial Transcription factor A (TFAM) is a protective coil wrapped around mitochondrial DNA (mtDNA) and acts to stabilize cardiomyocyte mtDNA via regulation of serca2a and lon protease. As observed in the literature loss of TFAM is negatively correlated with proteolytic activation of calpain and MMP's. Our preliminary data of healthy versus impaired cardiomyocytes suggests involvement of calpain-1, MMP9, TFAM and lon protease. Through western blotting and PCR analysis we found that up regulated protein and RNA expressions of calpain 1 and MMP 9 was negatively correlated with decreased expression of TFAM. TFAM's regulatory role over ROS production and calcium mishandling leads to our main hypothesis, that TFAM treatment to impaired cardiomyocytes will resuscitate physiological and potentially contractile activity of cardiomyocytes in CHF models. Exosomes are nanovessicles acting as biomolecular conservatories transporting mRNA, miRNA, proteins and nucleic acids. Exosomal delivery of TFAM to an AVF mouse model of CHF will ameliorate impaired cardiomyocytes and delay heart failure. Current literature focused on the molecular functions of TFAM, support this claim. Hypothesis: Exosomal delivery of TFAM will improve cardiomyocyte survival by mitigating mitochondrial dysfunction found in CHF.
Aims Proposed in F31 Kirschstein Pre-doctoral Fellowship (PA-14-148):
Aim #1 : To determine whether the mitochondrial transcription factor A contributes to cardiomyocyte function.
Aim#2 : To rehabilitate impaired cardiomyocytes via exosomal delivery of mitochondrial transcription factor A in chronic heart failure. This is a novel study utilizing an exosomal vehicle for TFAM treatment of chronic heart failure. Ameliorating effects of this treatment are promising based on the literature and preliminary studies. This proposal is clinically relevant and if successful, will significantly impct the treatment of heart failure patients.
Understanding the role of mitochondrial transcription factor A (TFAM) in cardiomyocyte function could provide important insight into chronic heart failure. Loss of TFAM is observed in cardiomyopathies and the literature states that TFAM transgenic models are cardioprotective. This project seeks to explore the cardioprotective therapeutic potential of TFAM packed exosomes on chronic heart failure.
| Kunkel, George H; Kunkel, Christopher J; Ozuna, Hazel et al. (2018) TFAM overexpression reduces pathological cardiac remodeling. Mol Cell Biochem : |
| Kunkel, George H; Chaturvedi, Pankaj; Thelian, Nicholas et al. (2018) Mechanisms of TFAM-mediated cardiomyocyte protection. Can J Physiol Pharmacol 96:173-181 |
| Theilen, Nicholas T; Kunkel, George H; Tyagi, Suresh C (2017) The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy. J Cell Physiol 232:2348-2358 |
| Kunkel, George H; Chaturvedi, Pankaj; Tyagi, Suresh C (2016) Mitochondrial pathways to cardiac recovery: TFAM. Heart Fail Rev 21:499-517 |
| Familtseva, Anastasia; Chaturvedi, Pankaj; Kalani, Anuradha et al. (2016) Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension. Am J Physiol Cell Physiol 311:C596-C606 |
