Role of aldehydes and oxidative stress generated by monoamine oxidase-A in cardiac failure associated with aging – CARDIOMAO

Heart failure (HF) is a clinical syndrome in which pathological stress or injury is associated with a failure of cardiac performance to meet the metabolic demands of the body. Age is a major risk factor for HF, at least in part because it prolongs exposure to hypertension, diabetes and other cardiovascular risks. However, intrinsic cardiac aging, the slowly progressive structural changes and functional declines with age also makes the heart more susceptible to stress and contributes to increased cardiovascular mortality in the elderly.
HF is the end consequence of a “long-term” cardiac remodelling. In the early phase, ventricular remodelling is a physiological compensatory response mainly characterized by cardiomyocyte hypertrophy. Late remodelling, characterized by cardiomyocyte loss and fibrotic response, leads to progressive HF. One of the major pitfalls in treating HF is a lack of appropriate explanation on the mechanisms responsible for myocardial decompensation. Thus, every step toward this goal will represent a new therapeutic potential to avoid decompensation and increase patient survival. Reactive oxygen species (ROS) appear to play a prominent role in triggering and maintaining ventricular damage, thus accelerating the progression of HF. Indeed, it has been shown that enhanced oxidative stress is involved in myocyte death in the aging heart. In addition, progression of cardiac damages in animals is attenuated by the administration of antioxidants. Therefore, it has been proposed that oxidative stress plays an important role in cardiac remodelling, by precipitating the progression from hypertrophy to failure.
The mitochondrial monoamine-degrading enzyme monoamine oxidase (MAO)-A has recently been identified as a major source of ROS in the heart. Besides its classical role in the degradation of monoamines (5-HT, catecholamines), cardiac MAO-A is also involved in receptor-independent effects of 5-HT, by generating hydrogen peroxide (H2O2). In rat cardiomyocytes, depending on the concentration of substrate, ROS generated by MAO-A can induce cardiomyocyte apoptosis or necrosis. In addition, we showed that cardiac MAO-A was strongly upregulated in human dilated cardiopathy (unpublished data) and in the aging heart. These observations prompted us to analyse the consequences of MAO-A upregulation in cardiomyocytes. For this purpose, we generated two independent lines of transgenic mice with cardiac-specific overexpression of MAO-A. We found that transgenic mice died prematurely from HF due to enhanced oxidative stress and myocyte drop-out (unpublished data). These results prompted us to hypothesize that MAO-A may be a death and senescence-associated factor in the heart.
In this proposal, our goal is to better understand the mechanisms of action of MAO-A metabolites (ROS and aldehydes) in the transition from hypertrophy to failure and in oxidative damage associated with aging. This project will have complementary in vitro and in vivo approaches. In vitro experiments will be performed on rat neonatal cardiomyocytes infected with MAO-A adenovirus to evaluate: 1) the participation of biogenic aldehydes generated by MAO-A in cardiomyocyte death; 2) the apparition of senescence markers following MAO-A overexpression; 3) the potential of MAO-A inhibitors in preventing cardiomyocyte death induced by pro-apoptotic agents. For our in vivo studies, we will evaluate the role of aldehyde in the development of HF induced by aortic banding or by MAO-A overexpression in mice, by treating mice with different carbonyl scavengers. The evolution toward HF will be followed, together with the apparition of senescence markers. The role of MAO-A in the transition from hypertrophy to failure will be evaluated by using selective MAO-A inhibitors in these same models.
This project should help us understand the importance of oxidative stress and aldehydes in the development of HF associated with MAO-A, and give new therapeutics directions