Abstract TAC280: Deletion of AT 1 Rs in Cholinergic Neurons Alters Cardiac Function and Remodeling During Chronic Angiotensin II Infusion in Male Mice

Introduction: The renin-angiotensin system plays a key role in autonomic function. Emerging evidence shows that the angiotensin II (Ang II) type 1 receptor (AT 1 R) is expressed in cholinergic neurons, yet its role remains unclear. We hypothesized that ablating AT 1 R expression in cholinergic neurons would disrupt autonomic regulation but confer protection against Ang II mediated hypertension and cardiac dysfunction. Methods: To test this, we crossed Chat -Cre and AT 1 R-Flox mice to generate mice with a cholinergic neuron-specific deficiency of the Agtr1a gene (KO). Age/sex-matched Cre- littermates were used as controls (WT). A slow pressor dose of Ang II (490 ng/kg/min) was continuously administered via osmotic minipump for 3 weeks. Radiotelemetric blood pressure (BP) and heart rate (HR), and echocardiographic data were compared at baseline and 3 weeks-post Ang II infusion in male mice. Results: At baseline we observed a modest but significant decrease in dark-cycle HR (WT: 629±8 bpm vs KO: 601±7; p=0.02; n=6/7). No significant differences in light-cycle HR, BP, and cardiac function by echocardiography was observed under baseline conditions. After 3 weeks of Ang II infusion, 24-hour systolic BP in both groups rose significantly from baseline in a genotype-independent manner (WT: from 128±3 to 155±9 mmHg vs KO: from 131±4 to 148±6; p treatment =0.003; n=3-7). Concomitant with elevated BP, Ang II induced cardiac dysfunction as measured by a decreased stroke volume. Interestingly, ablation of AT 1 R from cholinergic neurons ameliorated Ang II-induced cardiac dysfunction (WT: 28±1%; KO: 36±1; p=0.01; n=8/6). However, this beneficial effect occurred at the expense of enhanced cardiac remodeling evidenced by an increased left ventricular mass (WT: 184±14 mg; KO: 282±21 mg; p<0.0001; n=8/6), concentricity index (WT: 51±4 mg/uL; KO: 69±6; p=0.002; n=8/6), and a trend towards an increase in chamber dilation (WT: 2.0±0.3 uL/g; KO: 2.6±0.2; p=0.15; n=8/6). Conclusion: These data suggest that at the examined timepoint, ablation of the AT 1 R in cholinergic neurons confers a unique cardiac remodeling response to chronic Ang II. This response is characterized by a mixed concentric and eccentric hypertrophic phenotype that maintains cardiac function despite the elevated afterload. Further investigation is warranted to assess the durability of this protective effect during prolonged Ang II infusion and to distinguish the relative contributions of central and peripheral AT 1 R signaling.