Research ArticleCardiology Open Access | 10.1172/jci.insight.162602

Lu Ren,1,2 Phung N. Thai,1,3 Raghavender Reddy Gopireddy,4 Valeriy Timofeyev,1 Hannah A. Ledford,1 Ryan L. Woltz,1,3 Seojin Park,5,6 Jose L. Puglisi,7 Claudia M. Moreno,8,9 Luis Fernando Santana,8 Alana C. Conti,10,11 Michael I. Kotlikoff,12 Yang Kevin Xiang,3,4 Vladimir Yarov-Yarovoy,8 Manuela Zaccolo,13 Xiao-Dong Zhang,1,3 Ebenezer N. Yamoah,5 Manuel F. Navedo,4 and Nipavan Chiamvimonvat1,3,4

1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

Find articles by Kotlikoff, M. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

Find articles by Yarov-Yarovoy, V. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

Find articles by Zaccolo, M. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

Find articles by Zhang, X. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.

2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

3Department of Veteran Affairs, Northern California Health Care System, Sacramento, California, USA.

4Department of Pharmacology, UCD, Davis, California, USA.

5Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, Nevada, USA.

6Prestige Biopharma Korea, Myongjigukje 7-ro, Gangseo-gu, Busan, South Korea.

7College of Medicine. California North State University, Sacramento, California, USA.

8Department of Physiology and Membrane Biology, UCD, Davis, California, USA.

9Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.

10Research & Development Service, John D. Dingell VA Medical Center, and

11Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

12College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.

13Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.

Address correspondence to: Nipavan Chiamvimonvat, Manuel F. Navedo, or Ebenezer N. Yamoah. Phone: 530.754.7158; Email: nchiamvimonvat@ucdavis.edu (NC); Email: mfnavedo@ucdavis.edu (MFN); enyamoah@gmail.com (ENY).

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Published November 22, 2022 - More info

Published in Volume 7, Issue 22 on November 22, 2022
JCI Insight. 2022;7(22):e162602. https://doi.org/10.1172/jci.insight.162602.
© 2022 Ren et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published November 22, 2022 - Version history
Received: June 13, 2022; Accepted: October 5, 2022 View PDF Abstract

Sinoatrial node (SAN) cells are the heart’s primary pacemaker. Their activity is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the production of cAMP. There are current gaps in our knowledge regarding the dominant AC isoforms and the specific roles of Ca2+-activated ACs in the SAN. The current study tests the hypothesis that distinct AC isoforms are preferentially expressed in the SAN and compartmentalize within microdomains to orchestrate heart rate regulation during β-AR signaling. In contrast to atrial and ventricular myocytes, SAN cells express a diverse repertoire of ACs, with ACI as the predominant Ca2+-activated isoform. Although ACI-KO (ACI–/–) mice exhibit normal cardiac systolic or diastolic function, they experience SAN dysfunction. Similarly, SAN-specific CRISPR/Cas9-mediated gene silencing of ACI results in sinus node dysfunction. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) channels form functional microdomains almost exclusively with ACI, while ryanodine receptor and L-type Ca2+ channels likely compartmentalize with ACI and other AC isoforms. In contrast, there were no significant differences in T-type Ca2+ and Na+ currents at baseline or after β-AR stimulation between WT and ACI–/– SAN cells. Due to its central characteristic feature as a Ca2+-activated isoform, ACI plays a unique role in sustaining the rise of local cAMP and heart rates during β-AR stimulation. The findings provide insights into the critical roles of the Ca2+-activated isoform of AC in sustaining SAN automaticity that is distinct from contractile cardiomyocytes.

Graphical Abstract Introduction

Sinoatrial node (SAN) dysfunction (SND) results in an inability of the heart’s natural pacemaker cells to produce a normal rhythm. The prevalence is approximately 1 per 1,000 person years (1, 2) with a projected incidence of 172,000 people per year by 2060 (3), due to an ageing population. SND has a broad etiologic spectrum and affects children with congenital heart diseases, as well as the elderly (4, 5). However, there are significant knowledge gaps in our current understanding of SAN functions and its regulation.

SAN, the pacemaker of the heart, is the primary determinant of heart rate (HR) (6, 7) and is tightly regulated by β-adrenergic receptor (β-AR) signaling (8–10). Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the reaction to convert ATP into cAMP, resulting in a cascade of downstream effects (9, 11, 12). ACs are genetically diverse and encoded by 10 distinct genes. Nine ACs are transmembrane proteins, while 1 is a cytosolic form (11, 13).

The function of different isoforms of AC is directly dependent on the concentrations of intracellular Ca2+; ACI (Kd = 100 nM) (14) and ACVIII (Kd = 500 nM) (15) are Ca2+-activated isoforms, while physiological concentrations of Ca2+ inhibit ACV-VI (16). The genetic diversity suggests that different isoforms may serve distinct functions in specific regions of the body. The distribution of the AC isoforms may differ significantly between the SAN and working cardiomyocytes. In ventricular cardiomyocytes, the 2 Ca2+-inhibited isoforms, ACV and ACVI, are the 2 main isoforms (17). In contrast to ventricular myocytes, previous studies suggest the expression of Ca2+-activated AC isoforms in the SAN (18, 19). However, the functional roles and compartmentalization of Ca2+-activated AC isoforms in the SAN remain incompletely understood.

Ca2+ is an essential key modulator of the SAN’s pacemaker potential via the Ca2+ clock (20), during which Ca2+ is spontaneously released from the sarcoplasmic reticulum (SR) via ryanodine receptor 2 (RyR2), triggering the extrusion of Ca2+ from the cytosol via the Na+-Ca2+ exchanger (NCX). NCX exchanges 1 Ca2+ ion for 3 Na+ ions, generating an overall net inward current that contributes to diastolic depolarization (20).

To gain a mechanistic understanding of how the SAN function is regulated, we tested the hypothesis that distinct AC isoforms are preferentially expressed and compartmentalized in the SAN to serve a specialized function. Specifically, activated ACI increases cAMP concentrations, leading to an elevation of intracellular Ca