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GJA1-20k attenuates Ang II-induced pathological cardiac hypertrophy by regulating gap junction formation and

Yi-le Fu¹, Liang Tao¹, Fu-Hua Peng¹

¹Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.

Acta Pharmacologica Sinica

|July 5, 2020

Insights

This study reveals that GJA1-20k protein is crucial for maintaining cardiac function by regulating gap junction coupling and mitochondrial health in cardiac hypertrophy. Restoring GJA1-20k levels can be a potential therapeutic strategy for this condition.

Area of Science:

Cardiovascular Biology
Mitochondrial Medicine
Cellular Signaling

Background:

Cardiac hypertrophy (CH) involves cardiomyocyte enlargement and is a major cause of sudden cardiac death.
Reduced gap junction (GJ) coupling and mitochondrial dysfunction are key features of CH, but underlying mechanisms remain unclear.
GJA1-20k protein's role in connexin 43 (Cx43) trafficking and mitochondrial association suggests involvement in CH pathogenesis.

Purpose of the Study:

To investigate the impact of GJA1-20k on Cx43 GJ coupling and mitochondrial function in cardiac hypertrophy.
To explore the therapeutic potential of modulating GJA1-20k in CH.

Main Methods:

Utilized spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats for comparative analysis.
Employed hematoxylin-eosin (HE) and Masson staining to assess cardiac structure.
Utilized neonatal rat cardiomyocytes (NRCMs) for in vitro experiments involving gene overexpression, knockdown, and pharmacological inhibition (e.g., JAK-STAT pathway inhibitors).

Main Results:

SHRs exhibited significant cardiac hypertrophy, reduced Cx43 at intercalated discs, decreased GJA1-20k expression, and activated JAK-STAT signaling.
Valsartan treatment in SHRs reversed these pathological changes.
Overexpression of GJA1-20k in NRCMs attenuated Ang II-induced hypertrophy, enhanced GJ coupling, and improved mitochondrial function (membrane potential, respiration, ROS production).
JAK-STAT pathway inhibition normalized GJA1-20k expression and Cx43 GJ formation in hypertrophied NRCMs.

Conclusions:

GJA1-20k plays a critical role in regulating Cx43 gap junction formation and mitochondrial function during cardiac hypertrophy.
The JAK-STAT signaling pathway is implicated in the downregulation of GJA1-20k in CH.
Modulating GJA1-20k represents a promising therapeutic avenue for treating cardiac hypertrophy.

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Abstract:

Cardiac hypertrophy (CH) is characterized by an increase in cardiomyocyte size, and is the most common cause of cardiac-related sudden death. A decrease in gap junction (GJ) coupling and mitochondrial dysfunction are important features of CH, but the mechanisms of decreased coupling and energy impairment are poorly understood. It has been reported that GJA1-20k has a strong tropism for mitochondria and is required for the trafficking of connexin 43 (Cx43) to cell-cell borders. In this study, we investigated the effects of GJA1-20k on Cx43 GJ coupling and mitochondrial function in the pathogenesis of CH. We performed hematoxylin-eosin (HE) and Masson staining, and observed significant CH in 18-week-old male spontaneously hypertensive rats (SHRs) compared to age-matched normotensive Wistar-Kyoto (WKY) rats. In cardiomyocytes from SHRs, the levels of Cx43 at the intercalated disc (ID) and the expression of GJA1-20k were significantly reduced, whereas JAK-STAT signaling was activated. Furthermore, the SHR rats displayed suppressed mitochondrial GJA1-20k and mitochondrial biogenesis. Administration of valsartan (10 mg· [Formula: see text] d^-1, i.g., for 8 weeks) prevented all of these changes. In neonatal rat cardiomyocytes (NRCMs), overexpression of GJA1-20k attenuated Ang II-induced cardiomyocyte hypertrophy and caused elevated levels of GJ coupling at the cell-cell borders. Pretreatment of NRCMs with the Jak2 inhibitor AG490 (10 µM) blocked Ang II-induced reduction in GJA1-20k expression and Cx43 gap junction formation; knockdown of Jak2 in NRCMs significantly lessened Ang II-induced cardiomyocyte hypertrophy and normalized GJA1-20k expression and Cx43 gap junction formation. Overexpression of GJA1-20k improved mitochondrial membrane potential and respiration and lowered ROS production in Ang II-induced cardiomyocyte hypertrophy. These results demonstrate the importance of GJA1-20k in regulating gap junction formation and mitochondrial function in Ang II-induced cardiomyocyte hypertrophy, thus providing a novel therapeutic strategy for patients with cardiomyocyte hypertrophy.

Keywords:

GJA1-20k JAK-STAT angiotensin II cardiac hypertrophy gap junctions mitochondria

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