Cardiovascular dysfunction induced by combined exposure to nicotine inhalation and high fat diet

Abstract

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and smoking remains the most significant preventable risk factor. The contribution of nicotine, the addictive component of all tobacco products, to smoking-related CVD remains poorly understood. In addition to smoking, obesity is also a major risk factor for the development of CVD. Recent studies indicate that individuals who are overweight or obese are at greater risk of nicotine product usage. With more than 40% of the US population affected by obesity, the combined effects of obesity and nicotine on cardiovascular (CV) health warrant urgent investigation. In the present study we investigated the combined effects of nicotine exposure and a high fat diet (HFD) on CV function.Male C57BL/6N mice (8 wk-old) were placed on either a HFD (60 kcal% Fat) or standard chow (SC, 22 kcal% Fat) and exposed to room air (RA) or nicotine vapor (NIC, 12 hr/day during the active phase) for 10 weeks (n=10-15/group). Mice with HFD exposure alone exhibited significantly greater weight gain at 10 weeks vs. SC-RA controls (122.5±9.8% increase in body weight in HFD-RA vs. 40.7±3.3% in SC-RA, p < 0.0001), whereas concurrent nicotine inhalation significantly reduced this weight gain (66.5±5.8% in HFD-NIC group, p < 0.0001). In the HFD-NIC group, blood pressure (BP) monitoring via telemetry (24 hours) revealed non-significant increases in BP in the inactive phase, coupled with a significant (p < 0.05) reduction in the expected dipping in BP during the inactive compared to the active phase (HFD-NIC: 4.5±1.2; SC-RA: 11.3±2.2; HFD-RA: 12.4±1.0 and SC-NIC: 9.7±4.6 mmHg). LV catheterization showed that mice exposed to both nicotine and HFD had elevated LV end diastolic pressure (HFD-NIC: 14.1±0.7; SC-RA: 4.5±0.8; HFD-RA: 2.8±0.7 and SC-NIC: 3.9±1.3 mmHg; p<0.05) and prolonged time constant of LV relaxation (Tau). LV RNAseq analysis revealed that HFD-NIC resulted in 70 differentially expressed genes (36 upregulated and 34 downregulated) unique from nicotine or HFD alone, with multiple differentially regulated pathways including dilated cardiomyopathy signaling pathway (p = 2.8E-04). Plasma NT-pro-BNP levels were significantly increased in HFD-RA mice vs. SC-RA controls, whereas this response was absent in HFD-NIC. Finally, HFD+NIC led to greater impairment of endothelium-dependent vasorelaxation in thoracic aortas compared to either treatment alone.In conclusion, although nicotine reduced HFD-induced weight gain, combined exposure to inhaled nicotine and HFD led to greater cardiovascular dysfunction including dysregulation in physiological blood pressure responses, LV diastolic dysfunction, and greater impairment of endothelial-dependent vascular function. National Institute of Health [grant numbers HL135635 (to JDG, EL and XY); HL146098, HL146514, and HL151398 (to DJL.); and F30HL160071 (to AKW)]; Department of Veterans Affairs (BX004294 to EL) and the American Heart Association [Award 829761 (to AKW) and Award 20POST35200075 (to ZL)]. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.