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While the opioid epidemic has garnered significant attention, the use of methamphetamines is growing worldwide independent of wealth or region. Following overdose and accidents, the leading cause of death in methamphetamine users is cardiovascular disease, because of significant effects of methamphetamine on vasoconstriction, pulmonary hypertension, atherosclerotic plaque formation, cardiac arrhythmias, and cardiomyopathy. In this review, we examine the current literature on methamphetamine-induced changes in cardiovascular health, discuss the potential mechanisms regulating these varied effects, and highlight our deficiencies in understanding how to treat methamphetamine-associated cardiovascular dysfunction.

Proteinopathy causes cardiac disease, remodeling, and heart failure but the pathological mechanisms remain obscure. Mutated αB-crystallin (CryAB R120G ), when expressed only in cardiomyocytes in transgenic (TG) mice, causes desmin-related cardiomyopathy, a protein conformational disorder. The disease is characterized by the accumulation of toxic misfolded protein species that present as perinuclear aggregates known as aggresomes. Previously, we have used the CryAB R120G model to determine the underlying processes that result in these pathologic accumulations and to explore potential therapeutic windows that might be used to decrease proteotoxicity. We noted that total ventricular protein is hypoacetylated while hyperacetylation of α-tubulin, a substrate of histone deacetylase 6 (HDAC6) occurs. HDAC6 has critical roles in protein trafficking and autophagy, but its function in the heart is obscure. Here, we test the hypothesis that tubulin acetylation is an adaptive process in cardiomyocytes. By modulating HDAC6 levels and/or activity genetically and pharmacologically, we determined the effects of tubulin acetylation on aggregate formation in CryAB R120G cardiomyocytes. Increasing HDAC6 accelerated aggregate formation, whereas siRNA-mediated knockdown or pharmacological inhibition ameliorated the process. HDAC inhibition in vivo induced tubulin hyperacetylation in CryAB R120G TG hearts, which prevented aggregate formation and significantly improved cardiac function. HDAC6 inhibition also increased autophagic flux in cardiomyocytes, and increased autophagy in the diseased heart correlated with increased tubulin acetylation, suggesting that autophagy induction might underlie the observed cardioprotection. Taken together, our data suggest a mechanistic link between tubulin hyperacetylation and autophagy induction and points to HDAC6 as a viable therapeutic target in cardiovascular disease.P roteotoxicity is an important yet understudied mechanism in cardiac pathobiology (1), as maintaining tight control of protein homeostasis is critical for proper cell function. This is especially important in the unique context of the heart, as it is under constant mechanical and oxidative stress, and cardiomyocytes appear to be largely postmitotic soon after birth and are unable to readily regenerate (2, 3). Cellular stress events, including normal physiologic stimuli, can lead to altered cardiomyocyte function if the pathways of protein quality control (PQC) are compromised. Pathological cardiac stress, including pressure overload-induced hypertrophy and ischemia-reperfusion (I/R) injury, can alter protein degradation pathways (4-6). Our laboratory has developed a model of cardiac proteotoxicity based upon transgenically mediated cardiomyocyte expression of a mutated αB-crystallin (CryAB R120G ), which causes desminrelated cardiomyopathy in humans (7-9).CryAB is a molecular chaperone for desmin, an intermediate filament protein expressed in myocytes. Desmin is a crucial cardiomyocyte protein with vital signaling and structural ro...

Bhuiyan MS, Shioda N, Fukunaga K. Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats. Am J Physiol Endocrinol Metab 293: E1606-E1614, 2007. First published September 18, 2007; doi:10.1152/ajpendo.00246.2007.-To elucidate the molecular mechanism underlying estrogen-mediated cardioprotection in left ventricular (LV) hypertrophy and remodeling, we analyzed myocardial hypertrophy as well as cardiac function and hypertrophyrelated protein expression in ovariectomized, aortic-banded rats. Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis. Effects on LV morphology and function were assessed using echocardiography, and expression of protein levels was determined by Western blot analysis. The heartto-body weight ratio was most significantly increased in the OVXpressure overload (PO) group compared with the OVX group and in the PO group compared with sham. The LV weight-to-body weight ratio was also significantly increased in the OVX-PO group compared with the OVX group and in the PO group compared with sham. The most significant increases in LV end diastolic pressure, LV developed pressure, and Ϯdp/dtmax were observed in the OVX-PO group compared with the OVX group and represent compensatory phenotypes against hypertrophy. Both endothelial nitric oxide (eNOS) synthase expression and activity was markedly reduced in the OVX-PO group, and protein kinase B (Akt) activity was largely attenuated. Marked breakdown of dystrophin was also seen in hearts of OVX-PO groups. Finally, significantly increased mortality was observed in the OVX-PO group following chronic isoproterenol administration. Our results demonstrate that rats subjected to ovariectomy are unable to compensate for hypertrophy, showed deteriorated heart function, and demonstrated increased mortality. Simultaneous impairment of eNOS and Akt activities and reduced dystrophin by ovariectomy likely contribute to cardiac decompensation during PO-induced hypertrophy in ovariectomized rats. estrogen; myocardial hypertrophy; nitric oxide synthase EPIDEMIOLOGICAL STUDIES SHOW that the incidence of cardiovascular disease is higher in men than in premenopausal women but increases in postmenopausal women (10). Sex differences in left ventricular (LV) hypertrophy and remodeling have also been observed in aging and pressure-overloaded human hearts (4). It is suggested that, because of reduced estrogen levels after menopause, women lose an important cardiovascular protective mechanism and are at greater risk of developing hypertension (1). Moreover, estrogen has multiple protective effects on the cardiovascular system (27). However, the role of estrogen in development of cardiac hypertrophy is poorly understood. Most animal models of heart failure indicate that females resist cardiac contractile dysfunction (8,11,34). The relationship of sex and hypertrophy-induced heart failure is complex and depends on the model/etiology of hy...

Background The Sigma 1 receptor (Sigmar1) functions as an interorganelle signaling molecule and elicits cytoprotective functions. The presence of Sigmar1 in the heart was first reported on the basis of a ligand‐binding assay, and all studies to date have been limited to pharmacological approaches using less‐selective ligands for Sigmar1. However, the physiological function of cardiac Sigmar1 remains unknown. We investigated the physiological function of Sigmar1 in regulating cardiac hemodynamics using the Sigmar1 knockout mouse (Sigmar1 −/− ). Methods and Results Sigmar1 −/− hearts at 3 to 4 months of age showed significantly increased contractility as assessed by left ventricular catheterization with stimulation by increasing doses of a β 1 ‐adrenoceptor agonist. Noninvasive echocardiographic measurements were also used to measure cardiac function over time, and the data showed the development of cardiac contractile dysfunction in Sigmar1 −/− hearts as the animals aged. Histochemistry demonstrated significant cardiac fibrosis, collagen deposition, and increased periostin in the Sigmar1 −/− hearts compared with wild‐type hearts. Ultrastructural analysis of Sigmar1 −/− cardiomyocytes revealed an irregularly shaped, highly fused mitochondrial network with abnormal cristae. Mitochondrial size was larger in Sigmar1 −/− hearts, resulting in decreased numbers of mitochondria per microscopic field. In addition, Sigmar1 −/− hearts showed altered expression of mitochondrial dynamics regulatory proteins. Real‐time oxygen consumption rates in isolated mitochondria showed reduced respiratory function in Sigmar1 −/− hearts compared with wild‐type hearts. Conclusions We demonstrate a potential function of Sigmar1 in regulating normal mitochondrial organization and size in the heart. Sigmar1 loss of function led to mitochondrial dysfunction, abnormal mitochondrial architecture, and adverse cardiac remodeling, culminating in cardiac contractile dysfunction.