Autophagy in Hypertensive Heart Disease

Abstract

In response to hypertension, the heart manifests robust hypertrophic growth, which offsets load-induced elevations in wall stress. If sustained, this hypertrophic response is a major risk factor for systolic dysfunction and heart failure. Extensive research efforts have focused on the progression from hypertrophy to failure; however, precise understanding of underlying mechanisms remains elusive. Recently, autophagy, a process of cellular cannibalization, has been implicated. Autophagy is activated during ventricular hypertrophy, serving to maintain cellular homeostasis. Excessive autophagy eliminates, however, essential cellular elements and possibly provokes cell death, which together contribute to hypertension-related heart disease.Hypertension is a leading risk factor for mortality worldwide (1). Astonishingly, in 2000, Ͼ25% of the world's adult population was hypertensive (2). The hypertensive population is projected to reach 1.56 billion in 2025, a 60% increase over 25 years. Based on data from the latest National Health and Nutrition Examination Survey, 27% of American adults have hypertension as defined by a systolic blood pressure of 140 mm Hg or higher and/or a diastolic blood pressure of 90 mm Hg or higher (3). Moreover, recent studies highlight an important association between cardiovascular event rates and pre-hypertension, a state affecting Ͼ30% of the American population and defined as a systolic blood pressure between 120 and 139 mm Hg and/or a diastolic blood pressure between 80 and 89 mm Hg (3, 4). Because of the fact that hypertension provokes no symptoms, it is often neglected; it is estimated that one-third of hypertensive patients are not aware of their condition. Incomplete awareness plus barriers to treatment on both the patient and the care provider sides of the healthcare equation together add up to a disease with extraordinarily high prevalence and rising incidence. Indeed, it is difficult to conceive of an illness (hypertension plus pre-hypertension) that afflicts Ͼ60% of adults in the United States.Mounting epidemiological evidence demonstrates a linear and independent relationship between hypertension and CVD, 2 the leading cause of death worldwide (5). Ischemic heart disease and cerebrovascular disease account for more than one-fifth of mortality in both developing and developed countries (5). In the United States, one in three adults has one or more types of CVD, and a death results every 37 s (6). In 2008, the direct and indirect costs of CVD were estimated at $450 billion, an enormous burden to our economic and public health systems. Mechanisms of Remodeling in Hypertensive Heart DiseaseIncreased afterload precipitates increases in systolic wall stress within the pumping left ventricle. According to Laplace's law, wall stress is directly proportional to pressure and chamber size and inversely proportional to ventricular wall thickness (7). In response to high blood pressure, left ventricular wall thickness increases, normalizing wall stress. As post-mitotic cells, cardiomyocytes...

Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy

“…However, emerging evidence points to a requirement that autophagic activation remain fixed within a zone where its adaptive effects can take place (16,17); when autophagic flux is activated to excessive levels, or when it drops below a certain threshold, then pathological effects emerge (a phenomenon we have termed the "goldlilocks" zone of autophagy-not too much, not too little). Therefore, it is important to recognize that HDACi likely does not completely eliminate cardiomyocyte autophagy; rather, it suppresses autophagic flux without altering basal, constitutive levels of activation.…”

“…The myocardium comprises multiple cell types, all of which are capable of eliciting an autophagic response (17). To evaluate autophagy specifically in myocytes, we studied transgenic mice that express GFP-tagged LC3 under control of the cardiomyocyte-specific promoter αMHC (13).…”

“…Recent reports demonstrate that multiple forms of stress, including pressure overload, chronic ischemia, and ischemia-reperfusion provoke an increase in autophagic activity in cardiomyocytes (13)(14)(15)(16)(17). In the common clinical scenario of excessive afterload, autophagy is activated and contributes to disease pathogenesis (13,17). Thus, given that load-induced cardiomyocyte autophagy is maladaptive (13) and that HDACi is capable of blunting adverse remodeling (2-6), we hypothesized that maladaptive autophagy is HDAC dependent.…”

“…Conversely, dysregulation of autophagy contributes to the pathogenesis of several diseases, including neurodegenerative disorders, skeletal myopathy, cancer, and microbial infection (12). Recent reports demonstrate that multiple forms of stress, including pressure overload, chronic ischemia, and ischemia-reperfusion provoke an increase in autophagic activity in cardiomyocytes (13)(14)(15)(16)(17). In the common clinical scenario of excessive afterload, autophagy is activated and contributes to disease pathogenesis (13,17).…”

Replicated association between genetic variation in the PARK2 gene and blood pressure

“…Mutant Parkin has been reported to impair mitochondrial function and morphology in human cells [32]. Considering the fact that altered mitochondrial morphology has been suggested to be relevant to cardiovascular diseases [33,34] and autophagy has been implicated in cardioprotection [35][36][37], the previous findings suggest that the PARK2 gene may be closely linked with BP and hypertension phenotypes.…”