Mitochondrial AKAP1 Is Necessary for Obesity- and Angiotensin II-induced Hypertension

Abstract

Best known as the powerhouse of the cell, mitochondria play a crucial role in obesity and associated cardiovascular diseases. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that regulates mitochondria function by promoting protein kinase A (PKA)-mediated phosphorylation of Dynamin-related protein 1 at Ser637 through recruitment of PKA to the outer mitochondrial membrane. However, the role of mitochondrial AKAP1 in the regulation of blood pressure and the development of hypertension is not known. Here, we used mice harboring the Akap1 gene deletion to investigate the importance of AKAP1 in obesity- and angiotensin II (Ang II)-induced hypertension. AKAP1−/− mice and wild type (WT) littermates were maintained on a high fat high sucrose diet (HFHSD) for 12 weeks starting from 4 weeks of age. Interestingly, AKAP1−/− mice fed HFHSD displayed significantly attenuated weight gain compared to control mice fed HFHSD (male: 39.5 ± 1.7 vs 47.3 ± 2.3 g, and female: 29.7 ± 1.3 vs 32.5 ± 1.5 g, p<0.05 for both). This was associated with decreased fat mass in AKAP1−/− mice-fed HFHSD (male:16.2 ± 0.9 g and female: 8.7 ± 1.1 g) compared to controls (male: 21.2 ± 1.7 g and female: 13.9 ± 1.6 g, p<0.05 for both). Transmission electron microscope analysis of neuronal mitochondrial in the accurate nucleus of the hypothalamus showed that AKAP1−/− mice fed HFHSD have remarkably reduced mitochondria size (0.14 ± 0.05 vs 0.20 ± 0.07 μm2, p<0.05) and mitochondria length (0.57 ± 0.10 vs 0.50 ± 0.10 μm, p<0.05) relative to controls. Next, using the radio-telemetry system, we found that blood pressure was lower in AKAP1−/− male mice fed HFHSD compared to WT mice fed HFHSD (systolic: 118.2 ± 3.2 mmHg vs 126.7 ± 4.3 mmHg, p = 0.05, n= 5WT and 6 AKAP1−/−). Furthermore, infusion of Ang II (600ng/kg/min for 14 days) via osmotic minipumps in normal chow-fed male mice tended to evoke less increase in mean blood pressure in AKAP1−/− mice compared to WT controls (35.2 ± 3.5 vs 45.7 ± 10.1 mmHg, n=3). Taken together, our findings point to the importance of mitochondrial AKAP1 for the development of hypertension induced by obesity and Ang II. Veterans Affairs NIH. This is the full abstract presented at the American Physiology Summit 2024 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.