The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.

Pleiotropic Effects of Statins on the Cardiovascular System.

Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect pathways. Cardioprotective treatments are few and those that have been examined include renin angiotensin system blockade, beta blockers, or the iron chelator dexrazoxane. New treatments exploiting the ErbB or other novel pro-survival pathways, such as conditioning, are on the cardioprotection horizon. Even in the forthcoming era of targeted cancer therapies, the substantial proportion of today's anthracycline-treated cancer patients may become tomorrow's cardiac patient.

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Anthracycline Chemotherapy and Cardiotoxicity

The patient is a 63-year-old man with a history of well-controlled hypertension who is diagnosed with diffuse large B-cell lymphoma and treated with a doxorubicin-containing chemotherapy regimen. During therapy, he is continued on hydrochlorothiazide for his hypertension. Three months later, he

Cancer Therapy–Induced Cardiotoxicity: Basic Mechanisms and Potential Cardioprotective Therapies

Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy.

Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management

Aims Doxorubicin causes damage to the heart, often leading to irreversible cardiomyopathy, which is fatal. Reactive oxygen species (ROS) or oxidative stress is involved in cardiomyocyte death, contributing to doxorubicin-induced cardiotoxicity. This study investigated the role of Rac1, an important subunit of NADPH oxidase, in doxorubicin-induced cardiotoxicity and the underlying mechanisms.

Methods and results In a mouse model of acute doxorubicin-induced cardiotoxicity, cardiomyocyte-specific deletion of Rac1 inhibited NADPH oxidase activation and ROS production, prevented cardiac cell death, and improved myocardial function in Rac1 knockout mice. Therapeutic administration of the specific Rac1 inhibitor NSC23766 achieved similar cardio-protective effects in doxorubicin-stimulated mice. In rat cardiomyoblasts (H9c2 cells) and cultured neonatal mouse cardiomyocytes, Rac1 inhibition attenuated apoptosis as evidenced by decreases in caspase-3 activity and DNA fragmentation in response to doxorubicin, which correlated with a reduction in ROS production and down-regulation of p53 acetylation and histone H2AX phosphorylation. In contrast, overexpression of Rac1 enhanced apoptosis. Doxorubicin also inhibited the activity of classical histone deacetylases (HDAC), which was preserved by Rac1 inhibition and further decreased by Rac1 overexpression. Interestingly, scavenging ROS mitigated apoptosis but did not change HDAC activity and p53 acetylation stimulated by doxorubicin, suggesting both ROS-dependent and -independent pathways are involved in Rac1-mediated cardiotoxicity. Furthermore, the HDAC inhibitor trichostatin A enhanced apoptosis, p53 acetylation and H2AX phosphorylation in doxorubicin-treated cardiomyocytes.

Conclusions Rac1 signalling contributes to doxorubicin-induced cardiotoxicity through both a ROS-dependent mechanism and ROS-independent HDAC/p53 signalling in cardiomyocytes. Thus, inhibition of Rac1 may be a useful therapy for doxorubicin-induced cardiotoxicity.

Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways

Objectives Doxorubicin causes damage to the heart, often leading to irreversible cardiomyopathy, which is fatal. Reactive oxygen species (ROS) or oxidative stress is involved in cardiomyocyte death, contributing to doxorubicin-induced cardiotoxicity. This study was to investigate the role of Rac1, an important subunit of NADPH oxidase in doxorubicin-induced cardiotoxicity and the underlying mechanisms. Methods The models of doxorubicin-induced cardiotoxicity were created by challenging the mice with 20 mg/kg doxorubicin intraperitoneally. Cardiac function was determined by hemodynamic measurements. Cardiomyocytes apoptosis was assayed by caspase-3 activity assay and DNA fragmentation ELISA. ROS production was measured using DCF-DA molecule probe and NADPH oxidase was measured by an assay kit. We also used a HDAC assay kit to measure HDAC activity of cardiomyocytes. Results In a mouse model of acute doxorubicin-induced cardiotoxicity, cardiomyocyte-specific deletion of Rac1 inhibited NADPH oxidase activation and ROS production, prevented cardiac cell death and improved myocardial function in Rac1 knockout mice. Therapeutic administration of a specific Rac1 inhibitor NSC23766 achieved similar cardioprotective effects of Rac1 inhibition in doxorubicin-stimulated mice. In vitro studies using rat cardiomyoblasts H9c2 cells and neonatal mouse cardiomyocytes demonstrated that Rac1 inhibition attenuated apoptosis as determined by decreases in caspase-3 activity and DNA fragmentation in response to doxorubicin, which correlated with a reduction of ROS production and down-regulation of p53 acetylation and histone H2AX phosphorylation. Doxorubicin also inhibited the activity of classical histone deacetylases (HDAC), which was preserved by Rac1 inhibition. Interestingly, scavenging ROS mitigated apoptosis but did not change HDAC activity and p53 acetylation stimulated by doxorubicin, suggesting both ROS dependent and independent pathways are involved in Rac1-mediated cardiotoxicity. Furthermore, HDAC inhibitor trichostatin A enhanced apoptosis, p53 acetylation and H2AX phosphorylation in doxorubicintreated cardiomyocytes. Conclusions Rac1 signalling contributes to doxorubicin-induced cardiotoxicity through both ROS dependent mechanism and ROS independent HDAC/p53 signalling in cardiomyocytes. Thus, inhibition of Rac1 may be a useful therapy for doxorubicin-induced cardiotoxicity.

https://heart.bmj.com/content/heartjnl/98/Suppl_2/E21.3.full.pdf

Dong Zheng

Papers

Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways

Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species dependent and independent pathways