Protective Role of Kinin B1 Receptor Blockade in Angiotensin II-Induced Cardiac Mitochondrial Dysfunction

Background/Hypothesis: Mitochondrial dysfunction is increasingly recognized as a major driver of cardiovascular disease, making it a critical target for understanding and treating hypertension. Shifts in mitochondrial homeostasis have been observed in hypertension and affects major cellular processes including mitophagy, dynamics, and biogenesis. Previously, we found that elevated oxidative stress and reduced mitochondrial respiration by angiotensin (Ang) II can be abrogated by kinin B1 receptor (B1R) blockade in primary hypothalamic neurons. However, the role of B1R in mitochondrial functions in the heart during hypertension remain unexplored. Therefore, we hypothesized that B1R blockade will abate Ang II-induced mitochondrial dysfunction and cardiac damage. Approach: Male and female C57BL/6NJ wild-type (WT) and B1R global gene deficient mice (B1RKO) were implanted with telemetry transmitters to continuously monitor blood pressure and administered Ang II (600 ng/kg/min; SC, 4 weeks) or saline via osmotic minipumps (n=6 mice/sex/group). Hearts were then collected for further analysis. To complement our in vivo study, we cultured cardiomyocytes (CM, H9c2, ATCC) and human primary cardiac fibroblasts (HCF, PromoCell) and stimulated them with Ang II (300nM, 24h) with or without a B1R selective antagonist (R715, 10uM) (n=3-5 independent cultures/group). Results: Ang II increased mean arterial pressure (145 ±13 mmHg vs. 103 ±6, p<0.01), cardiac hypertrophy (HW:BW ratio and cardiomyocyte cross sectional area, p<0.0001), and remodeling (3-fold increase in Collagen) in WT mice, which were all attenuated in B1RKO mice. There were no significant differences in blood pressure between male and female B1RKO mice following Ang II. Hearts of WT mice with Ang II displayed elevated general (DHE, p<0.00001) and mitochondrial (MitoSOX, p=0.0002) oxidative stress as well as an imbalance of mitochondrial dynamics, indicated by an increase in fission (Drp1, p<0.0001) and reduced fusion (Mfn2, p<0.0001). B1RKO mice had a reduction of these effects, signifying that B1R plays a central role in mediating mitochondrial structure and cellular damage in the heart. In line with our in vivo data, we found elevated mitochondrial oxidative stress (MitoSOX, CM p<0.0001, HCF p=0.0002), dysregulated mitochondrial calcium handling (Rhod-2AM, CM p=0.0018, HCF p<0.0001) and a loss of mitochondrial membrane potential (TMRE, CM p<0.0001, HCF p<0.0001) in both cardiac cell types following Ang II, all of which are signs of a compromised and dysregulated mitochondria. B1R blockade reduced these effects, offering a restoration of mitochondria bioenergetics. Lastly, we identified that B1R plays a role in the degradation of mitochondria, as R715 reduced Ang II-induced mitophagy in human cardiac fibroblasts (LysoTracker: MitoTracker ratio, HCF p=0.0026). Conclusion: Together, these findings support the hypothesis that B1R activation contributes to mitochondrial dysfunction in hypertensive cardiomyopathy and that B1R inhibition can shift mitochondrial dynamics, biogenesis, and mitophagy towards homeostasis. Significance: These results highlight the potential for B1R as a novel therapeutic target to preserve mitochondrial integrity in patients with hypertension induced cardiac damage. This study was supported by the NHLBI/NIH 5R01HL153115 (S. Sriramula). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.