Agonism of Sirtuin 1 Attenuates Cardiac Dysfunction by Tobacco Smoking

About This Grant

Abstract Background and Innovation: Tobacco smoke is a major preventable cause of morbidity and mortality world- wide. It is estimated that >5 million people die from tobacco smoke-related illnesses each year. Smoking is a major independent risk factor for systemic injury, including atherosclerotic vascular disease, hypertension, my- ocardial infarction, unstable angina, sudden cardiac death, and stroke. While the association between chronic smoking and hypertension is recognized, the underlying mechanisms are incompletely understood. There is emerging evidence that a longevity protein sirtuin1 (SIRT1) can ameliorate blood pressure caused by cigarette smoking. Moreover, our group revealed that SIRT1 plays a critical role in cardioprotection against pressure overload-induced hypertrophy through modulating glucose and fatty acid metabolism and inflammatory re- sponse. Thus, it is hypothesized that pharmacological SIRT1 agonists can ameliorate smoking-induced cardi- ac dysfunctions of hypertension veterans’ patients via maintaining the metabolic and redox homeostasis in the heart. Two aims are proposed to test the hypothesis: Aim 1, to characterize the role of SIRT1 in cardiomyopa- thy by tobacco smoke and nicotine. Aim 2, to determine whether SIRT1 agonists ameliorate cardiac dysfunc- tions by smoking. The inducible cardiomyocytes specific SIRT1 knockout (icSIRT1-/-) and SIRT1f/f mice will be exposed to whole-body mainstream cigarette smoke using a SCIREQ smoking system. Age-matched, air- exposed mice will serve as nonsmoking controls. The pharmacological SIRT1 agonists will be used to deter- mine the critical role of SIRT1 in ameliorating blood pressure caused by cigarette smoking. In this manner, we will advance our understanding of the mechanisms underlying the cardiac SIRT1 signaling cascade in re- sponse to smoking-induced pathological stress. This grant seeks the potential to discover new therapeutic strategies to limit myocardial dysfunction caused by cigarette smoking in hypertension veterans’ patients. Significance and Impact to Veterans Healthcare: Cigarette smoking is a significant health problem within the US military. The prevalence of smoking was estimated among veterans with self-reported, physician- diagnosed coronary heart disease (CAD). Mounting evidence shows that there is an impaired signaling re- sponse to systemic stress in the hypertensive heart that leads to an increased susceptibility to smoking- induced pathology in these patients. Smoking cessation is critical for smokers with CAD, and clinicians have a responsibility to help patients with CAD reduce and ultimately quit smoking. The rates of current smoking sug- gest that more effective interventions may be necessary for veterans with CAD so that motivation to quit results in successful smoking cessation. Path to translation/implementation: This grant pursues to understand how impaired systemic signaling causes a higher incidence of cardiac dysfunctions by cigarette smoking in the veterans’ hypertension popula- tion and has the potential to discover new therapeutic strategies to limit myocardial dysfunction by cigarette smoking in these patients. Modifiable risk factors such as body-mas index, systolic blood pressure, low-density lipoprotein cholesterol level, tobacco smoking, and diabetes account for a percentage of the prevalence and incidence of cardiovascular disease. The definition of current smoking may not capture the entire spectrum and dose of tobacco exposure, and smoking cessation during follow up might have led to an underestimation of tobacco smoking as a risk factor. Targeting on a specific signaling pathway associated with cardiac dysfunction by cigarette smoking is a promising approach to reduce the risk of smoking related cardiovascular diseases in veterans.