Heme oxygenase-1 (HO-1), extracellular superoxide dismutase (ecSOD), and inducible nitric oxide synthase (iNOS) are interrelated stress-responsive proteins that are cardioprotective against acute ischemia/reperfusion injury. However, their role in chronic heart failure (HF) is not clear. The central objective of this Project is to unravel the pathophysiologic roles of HO-1, ecSOD, and iNOS in post-infarction HF using genetically modulated mice, and to determine whether these systems can be therapeutically manipulated for long-term benefit. Based on our preliminary studies, our central hypothesis is that in HF, Iong-term HO-1 and ecSOD induction are important beneficial adaptations that mitigate left ventricular (LV) remodeling. We further hypothesize that the effects of iNOS induction in HF depend on its cellular source, i.e., whereas myocyte iNOS is cardioprotective, inflammatory cell iNOS is detrimental. To test this hypothesis, we will perform four Specific Aims.
In Aim 1, we will define the cardiac expression of HO-1 and ecSOD in murine post-infarction HF, and its relationship to LV remodeling. We will then determine the effects of HO-1 loss- or gain-of function on LV remodeling via studies in HO-1 null mice and cardiac-specific HO-1 transgenic (TG) mice. Given the antioxidant and anti-apoptotic properties of HO-1, we will evaluate the effects of HO-1 modulation on oxidative stress, ecSOD expression, and apoptosis.
In Aim 2, we will evaluate the role of ecSOD in post-infarction LV remodeling, using ecSOD null mice and cardiac-specific ecSOD TG mice. As alterations in ecSOD would primarily impact extracellular free radicals, we will carefully examine, in addition to oxidative stress, the relationship between ecSOD modulation, matrix metalloproteinase activation, and dysregulation of the cardiac extracellular matrix.
In Aim 3, we will determine whether iNOS is beneficial or detrimental in HF, and establish the importance of the cellular source of iNOS. We will spatially and temporally define iNOS expression in post-infarction HF, and then evaluate the impact of iNOS loss- or gain-of-function on the HF phenotype using iNOS null and cardiac-specific iNOS TG mice. We will then examine mice with iNOS overexpression in the heart but with loss of iNOS in the periphery, to determine the role of myocyte versus inflammatory cell iNOS in HF. Finally in Aim 4, we will determine whether the protective effects of HO-1, ecSOD, and iNOS in post-infarction HF can be exploited therapeutically by the use of recombinant adeno-associated virus-mediated gene transfer. We will also evaluate whether the benefits of HO-1 gene therapy are lost in ecSOD null mice, thereby defining whether ecSOD is necessary for HO-1-mediated cardioprotection. Collectively, these studies will provide novel insights into the pathophysiologic roles of HO-1, ecSOD, and iNOS in HF, and will establish the mechanistic link between this cardioprotective system and oxidative/nitrative stress, apoptosis, and chamber remodeling post-infarction.
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