Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

Phosphodiesterase 3A ( ) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertro...

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Published in:	Circulation (New York, N.Y.) Vol. 146; no. 23; pp. 1758 - 1778
Main Authors:	Ercu, Maria, Mücke, Michael B., Pallien, Tamara, Markó, Lajos, Sholokh, Anastasiia, Schächterle, Carolin, Aydin, Atakan, Kidd, Alexa, Walter, Stephan, Esmati, Yasmin, McMurray, Brandon J., Lato, Daniella F., Yumi Sunaga-Franze, Daniele, Dierks, Philip H., Flores, Barbara Isabel Montesinos, Walker-Gray, Ryan, Gong, Maolian, Merticariu, Claudia, Zühlke, Kerstin, Russwurm, Michael, Liu, Tiannan, Batolomaeus, Theda U.P., Pautz, Sabine, Schelenz, Stefanie, Taube, Martin, Napieczynska, Hanna, Heuser, Arnd, Eichhorst, Jenny, Lehmann, Martin, Miller, Duncan C., Diecke, Sebastian, Qadri, Fatimunnisa, Popova, Elena, Langanki, Reika, Movsesian, Matthew A., Herberg, Friedrich W., Forslund, Sofia K., Müller, Dominik N., Borodina, Tatiana, Maass, Philipp G., Bähring, Sylvia, Hübner, Norbert, Bader, Michael, Klussmann, Enno
Format:	Journal Article
Language:	English
Published:	United States Lippincott Williams & Wilkins 06-12-2022
Subjects:	Animals Cardiomegaly Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism Heart Failure Humans Hypertension - complications Hypertension - genetics Induced Pluripotent Stem Cells - metabolism Myocytes, Cardiac - metabolism Rats RNA X-Ray Microtomography heart failure cyclic nucleotide phosphodiesterase, type 3 genetics cardiomegaly hypertension
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Summary:	Phosphodiesterase 3A ( ) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, mutations could be protective. We studied new patients. CRISPR-Cas9-engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying mutations were established, differentiated to cardiomyocytes, and analyzed by Ca imaging. We used Förster resonance energy transfer and biochemical assays. We identified a new mutation in a family with HTNB. It maps to exon 13 encoding the enzyme's catalytic domain. All hitherto identified HTNB mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The β-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the mutations caused adaptive changes of Ca cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. Although in vascular smooth muscle, mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-7322 1524-4539
DOI:	10.1161/CIRCULATIONAHA.122.060210